In The Name Of GOD Vascular Disorders Fatemeh Mokhtari Assistant Professor of Dermatology Vascular Biology Introduction The blood vessels of the skin: control of body temperature a conduit for the supply of nutrients and oxygen to the skin a conduit for the rapid disposal of metabolic waste products Blood and lymphatic vessels play essential roles in the development and progression of: skin tumors in physiologic processes: tissue repair hair follicle growth Markers for Blood Vessels In normal skin, the most specific markers for cutaneous blood vessels: CD34 PAL-E In normal adult skin, a receptor exclusively expressed on vascular endothelial cells and maintenance of the mature vascular architecture Tie-2 receptor Related Diseases Angiogenesis is a characteristic feature of: tissue repair numerous diseases inflammatory skin disorders: psoriasis and contact dermatitis cutaneous neoplasias: SCC, melanoma and Kaposi sarcoma infantile hemangiomas Related Diseases Several other diseases are characterized by prominent visible blood vessels: rosacea BCC Genetic mutations that lead to dysfunction of the vascular Tie-2 receptor: vascular malformations Vascular Anomalies According to the classification system adopted by the International Society for the Study of Vascular Anomalies (ISSVA), there are two types of vascular anomalies: vascular tumors vascular malformations Vascular Anomalies Vascular tumors cellular proliferation Vascular malformations errors in vascular morphogenesis characterized by the type of dysplastic vessels they contain and their flow properties Biologic Classification of Vascular Birthmarks Vascular Tumors Infantile hemangioma Congenital hemangioma (rapidly involuting or non-involuting variants) Kaposiform hemangioendothelioma Tufted angioma Pyogenic granuloma Congenital hemangiopericytoma Spindle cell hemangioma Biologic Classification of Vascular Birthmarks Vascular Malformations Capillary malformations (slow flow) Venous malformations (slow flow) Lymphatic malformations (slow flow) Arteriovenous malformations (fast flow) Combined malformations (slow and/or fast flow) History Adopting specific terminology has allowed investigators: better categorize vascular birthmarks predict their clinical behavior and prognosis Vascular Tumors Infantile Hemangiomas The most common soft tissue tumor of infancy Infants with hemangiomas were more likely to be: female Caucasian low birth weight premature products of multiple gestation pregnancies born to older mothers Pathogenesis Several hypotheses have been proposed to explain their pathogenesis Several mechanisms under the control of multiple genes Pathogenesis Hemangioma Endothelial Cells: Origin, Defects and Signaling Placental Hypothesis Hypoxia and Other Extrinsic Factors Factors Influencing Natural History Hemangioma Endothelial Cells: Origin, Defects and Signaling Recent evidence suggests: hemangiomas may be derived from endothelial progenitor cells or multipotent stem cells During hemangioma formation, vasculogenesis as well as angiogenesis might occur Vasculogenesis: de novo formation of vessels from progenitor/stem cells Angiogenesis: formation of new vessels from existing ones Hemangioma Endothelial Cells: Origin, Defects and Signaling Familial hemangiomas: chromosome 5q Sporadic hemangiomas loss of heterozygosity of 5q Suggesting that gene(s) at this locus may be involved in Hemangioma formation Increased expression of the endothelial cell-specific Tie-2 tyrosine kinase Placental Hypothesis Hemangioma cells are either of placental origin (e.g. via embolization) or undergo differentiation toward a placental microvascular phenotype Glucose transporter protein-1 (GLUT-1) is expressed by: infantile hemangiomas during all phases of their development (proliferating, involuting, involuted) the placenta not by other vascular tumors or malformations Hypoxia and Other Extrinsic Factors A role for hypoxia in the pathogenesis of hemangiomas is supported by: their association with hypoxic placental changes prematurity/low birth weight (often caused by placental insufficiency) Hypoxia upregulates expression of GLUT-I and VEGF, leading to mobilization of endothelial progenitor cells Factors Influencing Natural History In the proliferative phase, hemangiomas express: markers of proliferation (e.g. proliferating cell nuclear antigen [PCNA]) increased levels of pro-angiogenic molecules such as VEGF and basic fibroblast growth factor (bFGF ) Indoleamine 2,3-dioxygenase (IDO): inhibits T-cell activation is highly expressed by macrophages, dendritic cells, the placenta and proliferating hemangiomas increased IDO activity protects proliferating hemangiomas from immune surveillance downregulation of IDO production may therefore have a role in involution Increased expression of angiogenesis inhibitors and apoptosis promoters has been observed in involuting hemangiomas Vascular Malformations Introduction Vascular malformations: localized defects of vascular morphogenesis caused by dysfunction in pathways regulating the formation of vascular channels during embryonic development have a quiescent endothelium do not exhibit the markers of endothelial cell proliferation seen in infantile hemangiomas during their proliferative phase Introduction Because vascular malformations are not truly proliferating lesions with cellular hyperplasia, the suffix "oma" (meaning "tumor") has been deemed inaccurate The terms "angioma", "lymphangioma" and "hemangioma" should no longer be used for vascular malformations Introduction Vascular malformations are subcategorized depending on: the predominant anomalous channels flow characteristics: slow-flow or fast-flow A slow-flow vascular malformation may be: capillary (CM) venous (VM) lymphatic (LM) Introduction A fast-flow vascular malformation combines arterial anomalies and arteriovenous shunting, creating the nidus of an arteriovenous malformation (AVM) Complex-combined vascular malformations are designated as: capillary-venous (CVM) capillary-lymphatic (CLM) capillary-lymphaticvenous (CLVM) lymphatic-venous (LVM) capillary-arteriovenous (C-AVM) lymphatic-arteriovenous (L-AVM) Pathogenesis Rare familial transmission of vascular malformations has allowed: mapping of susceptibility to certain inherited lesions to precise chromosomal locations identification of the associated gene and disease causing mutations discovery of the function of the encoded proteins clarification of the role the dysfunction plays in regulatory pathways Pathogenesis It remains to be determined if sporadic vascular malformations, which are far more frequent than familial ones, are caused by the same gene mutations Some data support this hypothesis Cutaneous and mucosal venous malformations (VMCM) AD; sporadic (with somatic mutations in lesional tissue) Such research brings hope of gene therapy or currently unimaginable novel treatment strategies THE END