Biomathematical and Biomechanical Modelingof the Circulatory and Ventilatory Systems

Volume 5

For further volumes:http://www.springer.com/series/10155

Marc Thiriet

Tissue Functioningand Remodeling in theCirculatory and VentilatorySystems

123

Marc ThirietProject-team INRIA-UPMC-CNRS REOLaboratoire Jacques-Louis Lions, CNRS UMR 7598Universite Pierre et Marie CuriePlace Jussieu 475252 Paris Cedex 05France

ISSN 2193-1682 ISSN 2193-1690 (electronic)ISBN 978-1-4614-5965-1 ISBN 978-1-4614-5966-8 (eBook)DOI 10.1007/978-1-4614-5966-8Springer New York Heidelberg Dordrecht London

Library of Congress Control Number: 2012952271

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Preface

“ παντες ανθρωπoι τoυ ειδεναι oρεγoνται ϕυσει.”[All men by nature desire to know.](Aristotle [−384 –−322], Metaphysics, Book I)

Modeling relies on access to data accumulated on any target object (configuration,structure, controlled functioning, fate under various types of stimuli, reaction tostresses that can be experienced, etc.). Knowledge is associated with a set ofconditions: truth, belief justification, reliability, and stability. Understanding doesnot necessarily bring certitude before validation, especially in the absence ofobservation data.

Volumes 1 to 4 of this series present events and their molecular participantsthat govern cell fate — intra-, auto-, juxta-, and paracrine — as well as possibleendocrine regulations upon diverse types of stimuli, in the context of modeling andsimulations. These events rely on cascades of chemical reactions that successivelyactivate signaling mediators within the cell, at the nanoscopic scale. At the micro-and mesoscopic scale, biological phenomena comprise isolated and collectivebehavior of cells in interaction with their environment, either apposed cells, or theextracellular matrix. The present volume, Volume 5, treats mural tissues of airwaysand blood and lymph vessels — events occurring at the mesoscopic scale that can betargeted by mathematical models. Subsequent volumes focus on diseases associatedwith air and blood flows (Vol. 6) and mechanics of these flows (Vol. 7). Volume 8 isa set of glossaries.

Biological tissues are made up of composite material with different cell types inan extracellular matrix. Both types of tissue constituents — cells and matrix — arereinforced by filaments and fibers. In addition, the extracellular matrix can containlamellae. Structural hierarchy relies on the multilevel structure of biological tissues.The smallest structural levels are related to biological components, i.e., macro-molecules (scale O[1] nm), microfibrils (O[1] and O[10] nm]), fibers (O[100] nm),lamellae (O[1–10] �m). The fifth structural level usually corresponds to tissueelementary structure (scale O[100] �m). Biological tissues are characterized by anoptimal combination of configuration and structure at a given time with appropriatechemical and physical features to achieve their functions.

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vi Preface

Biological tissues are capable of short- and long-term adaptation (remodeling)to applied constraints that causes change in configuration and structure. These con-straints include mechanical stresses. The mechanical behavior of biological tissuesdepends on (1) type of applied forces (tension, compression, shear, and torsion) andtheir possible combination; (2) loading orientation, magnitude, duration, and rate;(3) eventual periodicity (frequency); and (4) state of the surrounding environmentand organism that regulate perfusion (hence, temperature, moisture, etc.).

The rheological properties of a sample of biological tissues that are related totissue composition are usually described by a set of parameters (bulk, elasticity,and shear moduli in principal tissue directions;1 Poisson’s ratio, Lame’s parameters,bending stiffness, flexural modulus, ultimate tension, compression, and shearstress; etc.).

Even in normal conditions, biological tissues remodel to adapt to their environ-ment. For instance, the thickness of arterial walls in a given vessel section canvary in the azimuthal direction, as it depends on the local stress field applied bythe flowing blood. Tissue engineering that does not incorporate mechanical stressesfails.

Abnormal situations are also characterized by maladaptive tissue remodeling(Vol. 6). Surgical procedures such as grafting and minimally invasive, catheter-based implantation of medical devices such as stents aimed at correcting risky tissuegrowth can themselves trigger another type of aberrant tissue growth, such as intimalhyperplasia.

Especially when they aim at predicting organ functioning, disease evolution,and drug delivery up to cells with abnormal functioning, mathematical modelsnot only focus on cellular events, but also on biological tissues. Major scientificdevelopments in health technology are aimed at integrating available fragmenteddata and models to improve medical decision-making and actions (gestures), reducehealthcare costs, and optimize the design of implantable devices.

This strategy copes with many challenges. Among them, modeling that spanmultiple structural levels (from molecular to entire organ). Therefore, the three basic

1Viscoelastic materials exhibit a phase lag (φ ) between stress (c) and strain (e):

c = cmaxsin{ωt},e = emaxsin{ωt +φ}. (0.1)

Complex elastic (E∗) and shear (G∗) moduli

E∗ = ERe + ıEIm, G∗ = GRe + ıGIm, (0.2)

are expressed from tensile ({ERe,EIm}) and shear ({GRe,GIm}) storage (c/e · cosφ ) and loss(c/e · sinφ ) moduli. Storage and loss moduli represent stored and dissipated energy of viscoelastictissues, respectively. Moreover, viscoelastic materials can be described by a low and a highmodulus at high and low temperatures, respectively, and the storage modulus by a low and a highrate modulus.

Preface vii

natural sciences — biology, chemistry, and physics — interact with mathematicsto optimize proper descriptions of the functioning and regulation of air and bloodflows.

Multiscale computational models currently being tackled include: (1) the heartpump functioning in the normal and diseased states; (2) the transport of drugnanoparticles that target a specific body region; (3) the insertion of an implantablemedical device inside a blood vessel, and (4) the transfer of drugs across the arterialwall and of therapeutic aerosols within the lumen and walls of the respiratory tract.However, despite advances in modeling patient anatomy, biophysical models remaindifficult to efficiently personalize.

Whereas mathematical models focus on tissue behavior from the nanoscopicto the mesoscopic scale, biomechanical modeling and simulations concentrate onmacroscopic events. Pumps and conduits walls are constituted by various types ofbiological tissues. These living composite materials sense, transmit, and react toforces exerted by flowing physiological fluids, such as air and blood. The behaviorof cells and tissues is tightly coupled to flow pattern.

Major features of flows are described by the equations of mass and momentumconservation, the so-called Navier-Stokes equations. However, because of thecomplicated architecture of networks of large and mid-size airways and bloodvessels that are assumed to convey a homogenous fluid, the Navier-Stokes equationscannot be solved analytically and require numerical simulations.

In addition, both air and blood flow inside deformable conduits. Therefore, thefluid dynamics depend not only on the geometry of the computational domain, onthe boundary conditions applied at domain inlets and outlets,2 and on the values offlow governing parameters, but also on the constitutive law of vessel walls, as wellas that of blood, when a non-Newtonian behavior must be incorporated, i.e., in thepresence of stagnant flow regions.

Blood is propelled from cardiac ventricles into arterial trees during systole oncethe pressure difference between the ventricular and arterial sides of the ventriculo-arterial valves causes leaflet displacement and change in shape. Flow decelerationthen provokes valve closing. The structure of the valved orifice can be divided intofour main domains with their own geometrical and rheological properties: arterialroot, valve base, leaflet, and coaptation zone (contact surfaces). Therefore, couplingcardiac contraction to blood ejection requires tackling a strong contact phenomenon.

Heart electromechanical coupling provides a good example of a feedback loop.The electrochemical wave caused by activation and deactivation of a set of ionchannels, pumps, and exchangers on the surface of as well as inside nodal cellsand cardiomyocytes triggers the ventricular contraction that, in turn, strains nodalcells and cardiomyocytes, thereby influencing the activity of mechanosensitive ionchannels (mechanotransduction).

2Entry and exit segments should be extended in the vessel axis direction to limit the sensitivity tothe boundary conditions in the region of interest and take into account up- and downstream effectsof three-dimensional flows.

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The respiratory epithelium that covers the luminal face of airways secretes abilayered fluid-gel coating and surfactant in large and small ducts, respectively.Mucus in large airways clears entrapped particles from the respiratory tract.Surfactant permits a proper inflation and deflation of bronchioles and alveoli.

This set of textbooks devoted to Circulatory and Ventilatory Systems in theframework of Biomathematical and Biomechanical Modeling aims at providingbasic knowledge and state of the art on the biology and the mechanics of blood andair flows. The cardiovascular and respiratory systems are tightly coupled, as theirprimary function is the supply of oxygen (O2) to and removal of carbon dioxide(CO2) from the body’s cells.

The present volume comprises 14 chapters. These chapters focus on the bio-logical tissues of the cardiovascular and ventilatory apparati (i.e., histology) andtheir functioning. Chapter 1 covers blood, a concentrated suspension of circulatingcells in a solvent, the plasma. Blood is a peculiar type of connective tissue usedfor transport and body regulation. All blood cell lineages derive from hematopoieticstem cells (Chap. 2). Hematopoiesis thus aims at maintaining a steady cell densityin the blood circulation (source term). The structure and function of blood cells— erythrocytes, leukocytes, and thrombocytes — are described in chapter 3. Thecirculatory network is connected to a specialized plasma-recycling compartment,the lymph collector. The latter conveys the lymph in lymphatic vessels (Chap. 4).

Chapters 5 to 9 cover the structure and composition of the heart and vessel walls.Chapter 5 focuses on cardiomyocyte structure and function. Chapter 6 on heart wallhighlights nodal cells that constitute the cardiac natural pacemaker and conductionroutes for the propagation of the electrochemical command. Blood vessel walls arestudied in chapter 7 with a special emphasis on the blood–brain barrier. Chapter 8examines the activity of the vascular and respiratory smooth myocytes that regulatethe caliber of blood vessels and airways. Endothelial cell at the interface betweenthe flowing blood and vessel wall is assigned to chapter 9. These cells play a role inclotting, extravasation of flowing cells, and transduction of mechanical stresses intochemical cues. Mechanotransduction leads to the synthesis of several substancesthat regulate the vasomotor tone.

Chapter 10 presents the regulated development of blood (vasculo- and angiogen-sis) and lymph vessels (lymphangiogensis). Chapter 11 discusses some biologicalprocesses, such as tissue growth as well as remodeling and repair, which arecommon to any body’s tissue. The final two chapters are devoted to the coating of therespiratory tract. Chapter 12 focuses on the mucus layer that lies over a periciliaryfluid in large airways as well as in medium-sized and small bronchi, while chapter 13deals with the airway-lining surfactant in pulmonary acini.

Abbreviations and Notation

Common abbreviations such as “a.k.a.” (“also known as”) are used throughoutthe text to lighten sentences. Latin-derived shortened expressions are also widely

Preface ix

utilized: “e.g.” (exempli gratia) and “i.e.” (id est) mean “for example” and “in otherwords”, respectively. The notation mode of molecule aliases is introduced in theappendix.

A physical quantity associated with a given point in space at a given time can be:(1) a scalar uniquely defined by its magnitude; (2) a vector characterized by a mag-nitude, a support, and a direction represented by an oriented line segment definedby a unit vector; or (3) a tensor specified by a magnitude and a few directions. Toensure a straightforward meaning of symbols used for scalar, vectorial, and tensorialquantities, bold face upper and lower case letters T and v are used to denote a tensorand a vector, respectively, whereas both roman (plain, upright)-style upper and lowercase letters designate a scalar.

Acknowledgments

These books result from lectures given at University Pierre et Marie Curie inthe framework of prerequisite training of Master “Mathematical Modeling”, partof Master of “Mathematics and Applications”, Tbilisi State University, Centrede Recherches Mathmatiques,3 and Taida Institute for Mathematical Sciences,4

the latter two in the framework of agreements with the French National Institutefor Research in Computer Science and Control.5 These lectures mainly aim atintroducing students in mathematics to basic knowledge of biology, medicine,rheology, and fluid mechanics in order to conceive, design, implement, and optimizeappropriate models of biological systems at various length scales in normal andpathological conditions. These books may also support the elaboration of proposalsfollowing suitable calls of granting agencies. The author takes the opportunity tothank the members of ERCIM office (European Consortium of Public ResearchInstitutes) and all of the participant teams of the working group “IM2IM” that yieldsa proper framework for such proposals. The author thanks especially Springer staffmembers S.K. Heukerott and D. Packer for their help and comments.

The author, an investigator from the French National Center for ScientificResearch6 wishes to acknowledge members of the INRIA-UPMC-CNRS team,“REO”,7 of Laboratoire Jacques-Louis Lions,8 of CRM (Y. Bourgault, M. Delfour,A. Fortin, and A. Garon), being a staff member in these research units, as wellas C.S. Lin and T.W.H. Sheu from Taida Institute for Mathematical Sciences, andR. Botchorishvili from Department of Numerical Analysis of the Vekua Institute ofApplied Mathematics at the Tbilisi State University.

3CRM (www.crm.umontreal.ca).4TIMS (www.tims.ntu.edu.tw).5Institut National de la Recherche en Informatique et Automatique (INRIA; www.inria.fr).6Centre National de la Recherche Scientifique (CNRS; www.cnrs.fr).7www-roc.inria.fr/reo8LJLL (www.ann.jussieu.fr).

x Preface

The author also acknowledges the patience of his wife Anne, daughter Maud,sons Alrik and Damien, and their respective families (Julien, Jean, and Louis;Raphaelle, Matthieu, and Alexandre; Joanna and Frederic).

Contents

1 Blood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1 Blood Functions .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.2 Plasma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31.3 Plasma Constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

1.3.1 Electrolytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51.3.2 Glucids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61.3.3 Plasma Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71.3.4 Plasma Lipids and Lipoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . 81.3.5 Blood Gas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

1.4 Blood Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151.4.1 Blood Cell Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

1.5 Blood Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171.5.1 Blood Substitutes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171.5.2 Plasmapheresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

2 Hematopoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192.1 Hematopoietic Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

2.1.1 LSK Hematopoietic Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . 232.1.2 Hemangioblast. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

2.2 Biological Models of Hematopoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242.2.1 Arborescence Models of Hematopoiesis . . . . . . . . . . . . . . . . . 252.2.2 Lymphoid Progenitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

2.3 Stem Cell Niches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272.3.1 Types of Bone-Marrow Niches . . . . . . . . . . . . . . . . . . . . . . . . . . . 272.3.2 Cells of Bone Marrow Niches . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282.3.3 Crosstalk between Niche-Resident Cells. . . . . . . . . . . . . . . . . 29

2.4 Regulation of Hematopoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312.4.1 Transcription Factors of Hematopoiesis . . . . . . . . . . . . . . . . . 322.4.2 Hormones, Growth Factors, and Morphogens . . . . . . . . . . . 422.4.3 MicroRNAs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492.4.4 Other Regulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

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2.5 Mastocyte Formation .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502.6 Hematopoietic Stem Cells in Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . 51

3 Blood Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533.1 Immunophenotyping of Leukocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533.2 Vasculature as an Immunity Compartment. . . . . . . . . . . . . . . . . . . . . . . . . . 543.3 Proliferation and Mobilization of Blood Cells . . . . . . . . . . . . . . . . . . . . . . 55

3.3.1 Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553.3.2 Chemokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

3.4 Scaffold Proteins in Immunocytes .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573.5 Red Blood Capsules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

3.5.1 Formation, Maturation, and Clearance .. . . . . . . . . . . . . . . . . . 603.5.2 Shape. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623.5.3 Plasma Membrane.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633.5.4 Influence of Oxygen Content in the Local

Environment .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663.5.5 Oxygen Sensor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673.5.6 Blood Groups of the RBC Plasma Membrane . . . . . . . . . . . 673.5.7 Hemoglobin Solution in Erythrocytic Capsule . . . . . . . . . . 713.5.8 Iron Acquisition and Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

3.6 Platelets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833.6.1 Platelet Cytoskeleton . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843.6.2 Translational Machinery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843.6.3 Platelet Granules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843.6.4 Platelet Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863.6.5 Non-Genomic Function of Transcription Factors. . . . . . . . 873.6.6 Other Regulators of the Platelet Function .. . . . . . . . . . . . . . . 883.6.7 Inflammatory Platelet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

3.7 Granulocytes .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893.7.1 Basophils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893.7.2 Eosinophils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 923.7.3 Neutrophils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

3.8 Mastocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 973.8.1 Mastocyte Origin and Maturation . . . . . . . . . . . . . . . . . . . . . . . . 983.8.2 Mastocyte Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 993.8.3 Mastocyte Production and Types . . . . . . . . . . . . . . . . . . . . . . . . . 100

3.9 Lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063.9.1 Selection between CD4 and CD8 Coreceptors . . . . . . . . . . 1063.9.2 Sensing of Endo- and Exogenous Molecules . . . . . . . . . . . . 1073.9.3 Resistance to Oxidizing Environment .. . . . . . . . . . . . . . . . . . . 1083.9.4 PIP3 and IP4 Signals in Lymphocytes .. . . . . . . . . . . . . . . . . . . 1093.9.5 Immunological Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

3.10 T Lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1113.10.1 T-Lymphocyte Development.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1113.10.2 Antigen Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

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3.10.3 T-Lymphocyte Maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163.10.4 T-Lymphocyte Subpopulations . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

3.11 Innate Lymphocytes .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1433.11.1 Lymphoid Tissue-Inducer Cells . . . . . . . . . . . . . . . . . . . . . . . . . . 1453.11.2 ILC17 Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1463.11.3 NKR+ LTi-like Cells – ILC22 Cells . . . . . . . . . . . . . . . . . . . . . 1473.11.4 Nuocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1473.11.5 Natural Killer Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

3.12 B Lymphocytes .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1543.12.1 B-Lymphocyte Subpopulations .. . . . . . . . . . . . . . . . . . . . . . . . . . 1553.12.2 B-Lymphocyte Maturation Stages . . . . . . . . . . . . . . . . . . . . . . . . 1553.12.3 Antibodies and B-Cell Receptors. . . . . . . . . . . . . . . . . . . . . . . . . 1563.12.4 B-Cell Activation and Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . 1593.12.5 Main Regulators of B-Cell Proliferation

in Germinal Centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1603.12.6 B Cell–T Cell Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1603.12.7 Plasmocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

3.13 Monocytes and Macrophages .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1613.13.1 Monocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1623.13.2 Macrophages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

3.14 Dendritic Cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1703.14.1 Myeloid and Plasmacytoid Dendritic Cells . . . . . . . . . . . . . . 1723.14.2 Thymic Dendritic Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

3.15 Myeloid-Derived Suppressor Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

4 Lymph Drainage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1774.1 Lymphatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1794.2 Lymphoid Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

4.2.1 Thymus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1804.2.2 Spleen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1804.2.3 Other Secondary Lymphoid Tissues. . . . . . . . . . . . . . . . . . . . . . 1814.2.4 Tertiary Lymphoid Tissue – Mucosa-

Associated Lymphoid Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1824.2.5 Lymph Nodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

4.3 Lymph . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

5 Cardiomyocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1895.1 External Organization of Cardiomyocytes . . . . . . . . . . . . . . . . . . . . . . . . . . 1895.2 Internal Organization of Cardiomyocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

5.2.1 Sarcolemma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1905.2.2 Sarcoplasmic Reticulum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1945.2.3 Mitochondria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1965.2.4 Nuclear GPCRs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

5.3 Sarcomere.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2065.3.1 Myofibrils. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2085.3.2 Myosin Thick Filaments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

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5.3.3 Actin Thin Filaments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2105.3.4 Z Disc, a Stretch-Sensing Structure . . . . . . . . . . . . . . . . . . . . . . 2165.3.5 Main Sarcomeric Constituents. . . . . . . . . . . . . . . . . . . . . . . . . . . . 216

5.4 Cardiac Adenylate Cyclases and the cAMP Pathway . . . . . . . . . . . . . . 2265.5 Calcium Signals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

5.5.1 Calcium-Dependent Ion Carriers . . . . . . . . . . . . . . . . . . . . . . . . . 2275.5.2 Inositol Polyphosphate Messengers –

Phosphoinositide Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2285.5.3 Mitochondrial Calcium Uniporter . . . . . . . . . . . . . . . . . . . . . . . . 2295.5.4 Mechanotransduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2295.5.5 Sodium–Calcium Exchangers and Sodium–

Potassium Pumps. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2305.5.6 Normal and Impaired Calcium Signaling . . . . . . . . . . . . . . . . 230

5.6 Endocrine Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2325.6.1 Natriuretic Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2335.6.2 Hemojuvelin–Hepcidin Regulation. . . . . . . . . . . . . . . . . . . . . . . 240

5.7 Energy Supply and Reserve. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2405.8 Cardiomyocyte Adaptive Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

5.8.1 Mechanotransduction in CMC Hypertrophy .. . . . . . . . . . . . 2435.8.2 Chemical Regulators of CMC Hypertrophy . . . . . . . . . . . . . 244

5.9 Cardiomyocyte Orientation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2525.10 Ion Carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254

5.10.1 Voltage-Gated Sodium Channels . . . . . . . . . . . . . . . . . . . . . . . . . 2565.10.2 Sodium–Calcium Exchangers . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2575.10.3 Myocardial Calcium Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . 2585.10.4 Myocardial Potassium Channels . . . . . . . . . . . . . . . . . . . . . . . . . 2625.10.5 Calcium-Activated Chloride Channels . . . . . . . . . . . . . . . . . . . 268

6 Heart Wall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2716.1 Cardiogenesis and Cardiac Remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272

6.1.1 First and Second Heart Fields . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2746.1.2 Heart Growth Patterns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2766.1.3 Epithelial–Mesenchymal Transition. . . . . . . . . . . . . . . . . . . . . . 2766.1.4 Vasculo- and Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2776.1.5 Neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2786.1.6 Valvulogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2796.1.7 Postnatal Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2816.1.8 Regulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2826.1.9 Cardiac Progenitor Cells and Precursors . . . . . . . . . . . . . . . . . 294

6.2 Wall Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2996.2.1 Cardiofibroblasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3006.2.2 Telocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3036.2.3 Epicardial Adipose Tissue and Adipokines . . . . . . . . . . . . . . 3036.2.4 Heart Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3066.2.5 Conduction Paths of the Depolarization Wave. . . . . . . . . . . 308

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6.3 Cardiac Regulation of Energy Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . 3136.4 Main Ion Currents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314

6.4.1 Pacemaker Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3156.4.2 Ventriculomyocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322

6.5 Action Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3246.5.1 Sinoatrial Node Action Potential . . . . . . . . . . . . . . . . . . . . . . . . . 3256.5.2 Ventricular Action Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3286.5.3 Electrophysiological Myocyte Types . . . . . . . . . . . . . . . . . . . . . 3296.5.4 Repolarization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3316.5.5 Electrophysiology and Contraction Kinetics. . . . . . . . . . . . . 331

6.6 Excitation–Contraction Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3326.6.1 Intercellular and Cell-Matrix Adhesions .. . . . . . . . . . . . . . . . 3346.6.2 Troponins and Tropomyosin .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3346.6.3 Calcium Ion and Its Partners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3346.6.4 Zinc Ion and Its Partners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3376.6.5 Cyclic Adenosine Monophosphate . . . . . . . . . . . . . . . . . . . . . . . 3386.6.6 S100 Protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3396.6.7 Nervous Influences .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3396.6.8 Cell Excitability Adjustment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3426.6.9 Electromechanical Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

6.7 Nervous Inputs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

7 Vessel Wall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3497.1 Physical Environment .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3497.2 Vasculature Development .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3507.3 Wall Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351

7.3.1 Large Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3537.3.2 Small Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359

7.4 Blood–Brain Barrier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3617.4.1 BBB Restricted Permeability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3627.4.2 Neurovascular Units. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3647.4.3 Functional Hyperemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3667.4.4 Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3677.4.5 BBB Formation.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368

7.5 Other Cerebral Epithelial Barriers – Choroid Plexi. . . . . . . . . . . . . . . . . 3687.6 Perivascular Nerves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3697.7 Pericytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3697.8 Nervous Inputs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3717.9 ATP Signaling in Blood Vessel Walls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373

7.9.1 Extracellular ATP Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3747.9.2 Nucleotide Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3757.9.3 ATP Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375

7.10 Vascular Oxygen Sensing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3787.11 Wall Adaptability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379

xvi Contents

8 Smooth Myocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3818.1 Markers of Smooth Myocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382

8.1.1 Actin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3838.1.2 Tropomyosin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3838.1.3 Myosin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3838.1.4 Calmodulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3848.1.5 Caldesmon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3868.1.6 Calponin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386

8.2 Glycocalyx.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3868.3 Intrinsic Regulators of Smooth Myocyte Tone . . . . . . . . . . . . . . . . . . . . . 387

8.3.1 Caldesmon and Calmodulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3878.3.2 Arachidonic Acid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3888.3.3 G-Protein-Coupled Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3888.3.4 Guanylate Cyclases, Nitric Oxide,

and Natriuretic Peptides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3888.3.5 Inositol Trisphosphate Receptors

and Calcium Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3898.4 Airway Smooth Myocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

8.4.1 Mechanical Loading-Induced CytoskeletonRemodeling .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

8.4.2 Contractile and Proliferative Phenotype . . . . . . . . . . . . . . . . . 3938.4.3 Calcium Influx. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3938.4.4 Airway Smooth Myocyte Products . . . . . . . . . . . . . . . . . . . . . . . 3948.4.5 Hyperresponsiveness and Hypersensitivity . . . . . . . . . . . . . . 4028.4.6 Deep Inspiration as Bronchodilation Inducer .. . . . . . . . . . . 402

8.5 Vascular Smooth Myocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4058.5.1 Vascular Smooth Myocyte Subtypes . . . . . . . . . . . . . . . . . . . . . 4078.5.2 Mesangial and Juxtaglomerular Cells . . . . . . . . . . . . . . . . . . . . 4078.5.3 Vascular Smooth Myocyte Phenotypes . . . . . . . . . . . . . . . . . . 4088.5.4 Vascular Smooth Myocyte Uptake . . . . . . . . . . . . . . . . . . . . . . . 4178.5.5 Vascular Smooth Myocyte Activity . . . . . . . . . . . . . . . . . . . . . . 4178.5.6 Vascular Smooth Myocyte Production . . . . . . . . . . . . . . . . . . . 4238.5.7 Vascular Smooth Myocyte Migration . . . . . . . . . . . . . . . . . . . . 4258.5.8 Vasomotor Tone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429

9 Vascular Endothelium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4539.1 Endothelial Cell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454

9.1.1 Glycocalyx.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4569.1.2 Endothelial Cell Adhesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4579.1.3 Vascular Permeability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467

9.2 Endothelium Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4689.2.1 High Endothelial Venules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4689.2.2 Lymphatic Endothelium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4699.2.3 Endothelial Fenestrae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469

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9.3 Endothelial Progenitor Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4699.3.1 Hemangioblast. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4709.3.2 Endothelial Progenitor Cell – Circulating

Angiogenic Cell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4729.4 Endothelial Cell Migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4749.5 Molecular Expression in the Vascular Endothelium .. . . . . . . . . . . . . . . 474

9.5.1 Caveolae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4779.5.2 Nuclear Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4799.5.3 Examples of Endothelial Receptors . . . . . . . . . . . . . . . . . . . . . . 4799.5.4 Ion Carriers of Endothelial Cell . . . . . . . . . . . . . . . . . . . . . . . . . . 4859.5.5 Hormones and Vasoactive Substances . . . . . . . . . . . . . . . . . . . 4929.5.6 Adhesion Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4989.5.7 Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4999.5.8 Vessel Wall Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4999.5.9 Growth Factors and Regulators of Growth

Factor Signaling .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5049.5.10 MicroRNAs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5079.5.11 Angiogenesis Guidance Molecules . . . . . . . . . . . . . . . . . . . . . . . 5109.5.12 Blood Group Antigens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512

9.6 Transendothelial Mass Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5129.6.1 Flow-Dependent Transendothelial Transport . . . . . . . . . . . . 5139.6.2 Transport Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5149.6.3 Endothelial Permeability and Vascular Compartments . . 5229.6.4 Endothelial Permeability Regulation .. . . . . . . . . . . . . . . . . . . . 522

9.7 Extravasation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5359.7.1 Flowing Cell Adhesion to Endothelium.. . . . . . . . . . . . . . . . . 5369.7.2 Cell Movement over the Wetted Endothelial Surface . . . 5379.7.3 Integrin-Based Cell Adhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5389.7.4 Intracellular Signaling in Endothelial Cells . . . . . . . . . . . . . . 5389.7.5 Intracellular Signaling in Leukocytes . . . . . . . . . . . . . . . . . . . . 5399.7.6 Extravasation Steps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5409.7.7 Extravasation Modes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5439.7.8 Migration across Pericyte Sheath

and Basement Membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5449.7.9 Migration through Subendothelial Layer

and Interstitium.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5459.7.10 Regulation of Inflammation.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546

9.8 Hemostasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5489.8.1 Blood Coagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5539.8.2 Fibrinolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5619.8.3 Embolus Extravasation .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5629.8.4 Thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5629.8.5 Mathematical Modeling and Numerical Simulations. . . . 564

9.9 Effects of High-Density Lipoproteins on Endothelium . . . . . . . . . . . . 565

xviii Contents

9.10 Chemical and Mechanical Regulation of the Vasomotor Tone . . . . . 5669.10.1 Transducers of Mechanical Stresses. . . . . . . . . . . . . . . . . . . . . . 5709.10.2 Flow Chambers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5759.10.3 Nitric Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5789.10.4 Endothelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5829.10.5 Calcium Signaling in Vasomotor Tone Regulation . . . . . . 5839.10.6 Other Mechanotransduction Effects . . . . . . . . . . . . . . . . . . . . . . 5859.10.7 Other Aspects of the Regulation of the Vasomotor

Tone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5889.10.8 Hypoxic Vasoconstriction of Pulmonary Arteries . . . . . . . 5949.10.9 Hypoxic Vasodilation of Cerebral Arterioles . . . . . . . . . . . . 5949.10.10 Vasomotor Tone during Pregnancy .. . . . . . . . . . . . . . . . . . . . . . 5969.10.11 Modeling of Mechanotransduction in Arteries . . . . . . . . . . 596

10 Vasculature Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60510.1 Vasculogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60610.2 Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606

10.2.1 Stem, Progenitor, and Precursor Cellsin Angiogenesis and Neovascularization .. . . . . . . . . . . . . . . . 607

10.2.2 Involved Factors in Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . 60910.2.3 Endothelial Sprouting: Tip and Stalk Cells . . . . . . . . . . . . . . 60910.2.4 Other Modes of Vessel Formation and Remodeling .. . . . 61310.2.5 Lumenogenesis .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614

10.3 Arteriogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61510.4 Vasculature Compartments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616

10.4.1 Lumen Size and Vessel Architecture . . . . . . . . . . . . . . . . . . . . . 61610.4.2 Cost Functions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61610.4.3 Arteriovenous Differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616

10.5 Extracellular Matrix in Vessel Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . 61810.5.1 Growth Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61810.5.2 Protein Fragments and Peptidases

of the Extracellular Matrix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62010.5.3 Cell Adhesion Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62210.5.4 Fibulins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62410.5.5 Thrombospondins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62510.5.6 Matrix Metallopeptidases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62510.5.7 Transglutaminase and Carboxypeptidases . . . . . . . . . . . . . . . 62510.5.8 Collagen Prolyl 4-Hydroxylase .. . . . . . . . . . . . . . . . . . . . . . . . . . 626

10.6 Mediators of Vascular Formation .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62610.6.1 Navigation Signals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62610.6.2 Transcriptional Regulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63010.6.3 MicroRNAs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63410.6.4 Morphogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63610.6.5 Growth Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63910.6.6 Hormones and Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647

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10.6.7 G-Protein-Coupled Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65310.6.8 Regulators of Small GTPases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65410.6.9 Phosphoinositide 3-Kinase and

Phospholipase-C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65410.6.10 Protein Kinase-B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65510.6.11 Cyclooxygenases and Prostaglandins . . . . . . . . . . . . . . . . . . . . 65610.6.12 Tissue Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65710.6.13 Tissue Kallikrein and Kininogen . . . . . . . . . . . . . . . . . . . . . . . . . 65710.6.14 Gasotransmitters Hydrogen Sulfide and Nitric Oxide .. . 65810.6.15 Oxidative Stress and Inflammation .. . . . . . . . . . . . . . . . . . . . . . 66010.6.16 Mechanical Signals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661

10.7 Angiogenesis-Targeted Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66210.7.1 Angiogenesis Promotion .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66210.7.2 Angiogenesis Inhibition.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664

10.8 Lymphangiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66810.8.1 Transcription Factors in Lymphangiogenesis .. . . . . . . . . . . 66910.8.2 Growth Factors and Guidance Molecules . . . . . . . . . . . . . . . . 67010.8.3 Other Mediators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671

10.9 Modeling of Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671

11 Tissue Development, Repair, and Remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . 67511.1 Organogenesis .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676

11.1.1 Ecto-, Endo-, and Mesoderm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67611.1.2 Precursor Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67811.1.3 Organogenesis, Vascularization, and Innervation .. . . . . . . 67911.1.4 Regulation of Organogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680

11.2 Cell Differentiation .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68211.3 Branching Morphogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 682

11.3.1 Airway Morphogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68311.3.2 Airway Morphogenesis Mediators . . . . . . . . . . . . . . . . . . . . . . . 68411.3.3 Mechanical Basis of Branching . . . . . . . . . . . . . . . . . . . . . . . . . . 68811.3.4 Molecular Basis of Branching . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688

11.4 Therapeutic Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69211.4.1 Stem Cells and Regenerative Therapy . . . . . . . . . . . . . . . . . . . 69211.4.2 Gene Therapy.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69711.4.3 Tissue Engineering .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699

11.5 Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70311.5.1 Extravasation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70311.5.2 Molecular Basis of Extravasation . . . . . . . . . . . . . . . . . . . . . . . . 70411.5.3 Crossing of the Vascular Basement Membrane .. . . . . . . . . 71311.5.4 Interstitial Migration of Leukocytes . . . . . . . . . . . . . . . . . . . . . . 71311.5.5 Molecular Mechanisms of Leukocyte Chemotaxis . . . . . . 71311.5.6 Inflammatory Mediators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71511.5.7 Angiogenesis and Inflammation .. . . . . . . . . . . . . . . . . . . . . . . . . 72811.5.8 Inflammatory Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 730

xx Contents

11.6 Healing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73111.6.1 Plasma Enzymatic Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73211.6.2 Involved Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73211.6.3 Myofibroblasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73311.6.4 Healing Phases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73511.6.5 Modeling of Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737

11.7 Respiratory Epithelium Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73911.8 Vascular Tissue Remodeling .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 740

11.8.1 Myocardium Remodeling .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74111.8.2 Vessel Wall Remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742

11.9 Growth Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 745

12 Airway Surface Liquid and Respiratory Mucus . . . . . . . . . . . . . . . . . . . . . . . . 74912.1 Double-Layered Airway Surface Fluid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751

12.1.1 Control of the Quantity and Compositionof the Airway Surface Fluid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 752

12.2 Mucociliary Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75412.2.1 Factors of the Mucociliary Clearance . . . . . . . . . . . . . . . . . . . . 75512.2.2 Cough Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75512.2.3 Mucociliary Clearance and Infection.. . . . . . . . . . . . . . . . . . . . 75612.2.4 Alterations in Mucociliary Clearance . . . . . . . . . . . . . . . . . . . . 756

12.3 Mucus Delivery.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75812.3.1 Secretory Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75812.3.2 Mucus Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76612.3.3 Regulation of Mucus Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . 767

12.4 Mucus Composition .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76912.4.1 Mucin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77012.4.2 Other Proteic Constituents of Mucus .. . . . . . . . . . . . . . . . . . . . 77212.4.3 Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77312.4.4 Surfactant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77312.4.5 Minerals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773

12.5 Mucus Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77412.5.1 Mucus Permeability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77412.5.2 Mucus Contact Properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77512.5.3 Mucus Rheology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775

12.6 Mucus Motility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77812.6.1 Respiratory Cilium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77812.6.2 Cilium Beats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78012.6.3 Ciliogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785

12.7 Mucus Transport Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78612.7.1 Governing Equations .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787

13 Surfactant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78913.1 Surface Tension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78913.2 Alveolar Surfactant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794

13.2.1 Formation of the Alveolar Surface Film . . . . . . . . . . . . . . . . . 794

Contents xxi

13.2.2 Alveolar Liquid Film Homeostasis . . . . . . . . . . . . . . . . . . . . . . . 79513.2.3 Secretion and Role of Alveolar Surfactant . . . . . . . . . . . . . . . 796

13.3 Surfactant Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79713.3.1 Surfactant Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79713.3.2 Surfactant Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79913.3.3 Calcium .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 800

13.4 Immune Function of Surfactant. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80013.5 Governing Equations and Surfactant Transport Modeling . . . . . . . . . 800

13.5.1 Interfacial Tension and Marangoni Stress . . . . . . . . . . . . . . . . 80113.5.2 Dimensionless Governing Parameters. . . . . . . . . . . . . . . . . . . . 80113.5.3 Surfactant and Marangoni Flows . . . . . . . . . . . . . . . . . . . . . . . . . 802

14 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 813

Notation Rules: Aliases and Symbols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903

List of Currently Used Prefixes and Suffixes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909

List of Aliases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 913

Complementary Lists of Notations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 949