wyklad 2 12 03 2012

VascularVascular endothelialendothelial

growthgrowth factorfactor andand otherother

propro--angiogenic angiogenic factorsfactors

lecture II

12th March 2012

Oloffson et al., 2000

VEGF, VEGFVEGF, VEGF--AA

vascular endothelial growth factor

main regulator of angiogenesis, pro-angiogenic factor

1787 - Dr John Hunter first uses the term 'angiogenesis' to describe blood

vessels growth

1983 - Vascular Permeability Factor (VPF), is discovered by Dr Harold

Dvorak. The molecule VPF causes leaky blood vessels associated with tumors

VPF was 50 000 times more potent than histamine.

1989 - One of the most important angiogenic factors, vascular endothelial

growth factor (VEGF), is discovered by Napoleone Ferrara and by Jean Plouet.

It turns out to be identical to the molecule called Vascular Permeability Factor

(VPF) discovered in 1983 by Dr. Harold Dvorak.

Angiogenesis and VEGF “history”AngiogenesisAngiogenesis andand VEGF VEGF ““historyhistory””

VascularVascular

EndothelialEndothelial

GrowthGrowth

FactorFactor

VV

EE

GG

FF

VascularVascular

PermeabilityPermeability

FactorFactor

VV

PP

FF

1983,1983,

Dr H. Dr H. DvorakDvorak

1989, 1989,

Dr N. FerraraDr N. Ferrara

Dr J. Dr J. PlouetPlouet

=

vascularvascular permeabilitypermeability factorfactor

endothelialendothelial cellcell survivalsurvival factorfactor

endothelialendothelial cellcell proliferationproliferation

endothelialendothelial cellcell migrationmigration

MainMain proangiogenicproangiogenic factorfactor

Carmeliet, 2005; Semenza 2003

BloodBlood vesselvessel formationformation –– variousvarious waysways

VEGF VEGF belongsbelongs to VEGF to VEGF familyfamily

EndogenouslyEndogenously expressedexpressed inin mammalsmammals

EncodedEncoded by by thethe

double double strandedstranded

DNA DNA virusvirus, , orforf

VEGFVEGF--AA

VEGFVEGF

• VEGF (vascular endothelial growth factor,

vascular permeability factor, vasculotropin)

– homodimeric protein

• produced by many types of cells

(e.g. macrophages, VSMC, fibroblasts, and cancer cells)

• expression is induced in response to hypoxia and proinflammatory cytokines

• receptors (VEGF-R1 and VEGF-R2) are present mostly on endothelial cells,

therefore VEGF acts specifically on endothelium (but also on neurons and

Schwann cells).

• VEGF-R1 is expressed also on monocytes and vascular smooth muscle cells –

their activation upregulates expression of metalloproteinases and increases cell

migration.

VEGFVEGF

• It protects endothelial cells from apoptosis and induces their proliferation,

migration, and formation of capillaries

• VEGF acts protectively on neurons

• VEGF is required for the normal development of embryonic vasculature, the

cyclic growth of blood vessels in the female reproductive tract, and the

formation of capillaries during wound repair

• however, VEGF is also involved in abnormal angiogenesis, as seen in

proliferative retinopathies, rheumatoid arthritis, psoriasis, and malignancies

VEGF VEGF isis highlyhighly conservedconserved betweenbetween speciesspecies

VEGF has been found in all vertebrate species :

• fish (the zebrafish Danio rerio)

• frogs (Xenopus laevis)

• birds (Gallus gallus)

• mammals

The sequence and genomic organization of the vertebrate VEGF-A

genes is highly conserved between fish and mammals.

Fish VEGF-A shows 68% and 69.7% amino-acid identity with human and mouse

VEGF-A, respectively

Invertebrate VEGF/VEGFR systems have been identified in fly (Drosophila

melanogaster), nematode (Caenorhabditis elegans) and, most recently, in jellyfish

(Podocoryne carnea).

VEGF-like proteins are present in several invertebrate species

PresencePresence ofof VEGFVEGF--likelike proteinsproteins inin differentdifferent animalsanimals

• In the nematode Caenorhabditis elegans four possible

homologs of PDGF/VEGF receptors (VER-1 to VER-4) and

one ligand (PVF-1) are known

• PVF-1 has the ability to bind to human receptors VEGFR-

1 and VEGFR-2 and to induce angiogenesis in two model

systems derived from vertebrates

Jorgensen & Mango, Nat Rev Gen 2002; Tarsitano et al. FASEB J 2006.

Control HUVEC HUVEC + VEGF HUVEC + PVF-1

O’Farrell, J Clin Invest 2001

DrosophilaDrosophila melanogastermelanogaster

respiratory (respiratory (trachealtracheal) system) system

- Branching tubular system of trachea delivers oxygen to

the tissues of insects.

- Its development shows parallels to the angiogenesis

- Branchless (a homolog of mammalian FGF), PVF1, PVF2, PVF3 (homologs of

mammalian VEGF/PDGF) and PVR receptor regulate the migration of early

hemocytes and are necessary for formation of tracheal system.

Tracheal tree of Drosophila embryo

DB – dorsal branch; DT – dorsal trunk;

GB – ganglionic branch; VB – visceral branch

• The human VEGF-A gene is characterized by a highly conserved eight exon structure,

• Alternative splicing of the human VEGF-A gene gives rise to at least five different

transcripts encoding isoforms of the following lengths (in amino acids)

121, 145, 165, 189 and 206

OrganisationOrganisation ofof VEGF VEGF genegene andand VEGF isoforms VEGF isoforms

Exons 1-5 8

Exons 1-5 86A1 A2

Exons 1-5 87

VEGF-A121

VEGF-A145

VEGF-A165

VEGF-A189

VEGF-A206

Exons 1-5 876A1 A2

Exons 1-5 876A1 A2 6B

Sequestered in ECM but releasedby cleavage

1-8 plus additional exon206VEGF-A206


1-8189VEGF-A189


1-5, short exon 6, 7, 8183VEGF-A183

Secreted, endogenous inhibitory form of VEGF-A165

1-5, 7, alternative exon 8165VEGF-A165b

The most abundant and biologicallyactive isoform; secreted; binds

NRP1 and NRP2

1-5, 7, 8165VEGF-A165

Binds NRP2 but not NRP1; secreted1-6, 8145VEGF-A145

Secreted1-5, 8121VEGF-A121

FeaturesCoding exonsSize(amino acid)

Isoform

VEGF isoformsVEGF isoformsVEGF isoforms

PropertiesProperties ofof VEGF isoforms VEGF isoforms

VEGF121 is a soluble acid polypeptide

VEGF189 and VEGF206 are highly basic and bind very strongly

to heparin, thus they are completely sequestred in extra-

cellular matrix (ECM)

VEGF165 has intermediate properties: it is secreted, but significant

fractions remains bound to cell surface and ECM

ExpressionExpressionofof VEGF isoformsVEGF isoforms

• Most VEGF-producing cells express VEGF121, VEGF165, VEGF189,

and often VEGF183. VEGF206 is seemingly restricted to cells of

placental origin.

• VEGF165 is most abundantly expressed, but VEGF189 is a major

isoform in lungs, and both VEGF165 and VEGF189 predominate in

heart. Furthermore, the relative levels of VEGF isoforms may vary

during development or in response to cytokine stimulation.

Not Not everyevery cells cells expressexpress

thethe same same amountsamounts ofof VEGF VEGF

HASMC HMEC-primary HMEC-1 rat Müller cells

VEGF VEGF expressionexpression in in severalseveral cellcell lineslines -- intactintact cellscells

(24 h incubation)

MBEC ~ 300-400 pg/ml

HepG2 ~ 200 pg/ml

HMEC-1 ~ 20 pg/ml

165

121

ReceptorsReceptors for VEGFfor VEGF--AA

Main receptors:

VEGFR-1 (Flt-1)

VEGFR-2 (Flk1; KDR)

Accessory receptors

Neuropilin 1 (NRP1)

Neuropilin 2 (NRP2)

Storage

heparan sulfate proteoglycans

VEGFVEGF--AA belongsbelongs to VEGF to VEGF familyfamily

ReceptorsReceptors for VEGFfor VEGF--AABoth VEGF receptors have 7 immunoglobulin-like domains in the extracellular domains,

a single transmembrane region and a consensus tyrosine kinase sequence that is

interrupted by a kinase-insert domain.

The Biology of Cancer by R Weinberg

GrowthGrowth factorsfactors andand receptorsreceptors ofof thethe VEGF VEGF familyfamily

VEGFVEGF--R1R1 VEGFVEGF--R2R2 VEGFVEGF--R3R3

HeparanHeparan--SulfateSulfateProteoglycanProteoglycan

NeuropilinNeuropilin --11 NeuropilinNeuropilin --22

After Neufeld et al.. 1999, FASEB J 13:9-22

VEGF121VEGF121VEGF145VEGF145VEGF165VEGF165VEGF189VEGF189VEGFVEGF--BBPlGFPlGF--11PlGFPlGF--22

VEGF121VEGF121VEGF145VEGF145VEGF165VEGF165VEGFVEGF--CCVEGFVEGF--DDVEGFVEGF--EE

VEGFVEGF--CCVEGFVEGF--DD

VEGF145VEGF145VEGF165VEGF165VEGF189VEGF189VEGF206VEGF206VEGFVEGF--B167B167VEGFVEGF--EEPlGFPlGF--22

SemaSema--IIIIIISemaSema--EESemaSema--IVIVVEGF165VEGF165PlGFPlGF--22VEGFVEGF--BBVEGFVEGF--EE

SemaSema--EESemaSema--IVIVVEGF165VEGF165

TK

TK

ExpressionExpression ofof VEGF VEGF receptorsreceptors

- endothelial cells: VEGFR-1, VEGFR-2, co-receptors

- other cells:

monocytes

vascular smooth muscle cells

tumor cells

hematopoietic stem cells

neuronal cells

Ferrara et al. 2004Ferrara et al. 2004

VEGF VEGF receptorsreceptors –– role role inin angiogenesisangiogenesis

SignificanceSignificance ofof VEGF VEGF andand VEGF VEGF receptorsreceptors

hashas beenbeen recognizedrecognized by by targetingtargeting

disruptiondisruption ofof thosethose genesgenes inin mice mice

Ferrara & Alitalo, Nature Med. 1999

KnockoutKnockout ofof VEGF VEGF isis lethallethal inin heterozygousheterozygous form form

Yolk sac of E10.5 VEGF+/+ and VEGF +/– mouse embryos

EffectEffect ofof knockoutknockout ofof VEGF VEGF receptorsreceptors

Flt1-/- mice die in utero between days 8.5 and 9.5

- EC develop but do not organize into vascular channels

- excessive proliferation of angioblasts

VEGFR-1

VEGFR-2

Flk1-null mice die between day 8.5 and 9.5

Lack of vasculogenesis and failure to develop blood islands

and organized blood vessels

SemaphorinSemaphorin receptorsreceptors –– NpNp--1 1 andand NpNp--2 2

- form complexes with type A plexins

- complexes serves as signaling receptors for class-3 semaphorins

- involved in axonal guidance

Np-1 and Np-2 in angiogenesis

- binds VEGF165, VEGF-B, PlGF-2

- knockout of Np-1 – lethal at E12.5

- overexpression of Np1- excessive capillary formation, dilated blood vessels

extensive hemorrhage

- no visible abnormalities in Np-2 knockout mice, but Np-2-/- Np1+/- are lethal

- double knockouts Np-1-/-Np-2-/- died in utero at E8.5, completely avascular

yolk sacs

Functions of the VEGF receptors familyFunctions of the VEGF receptors family

Found only in lymphatic endothelial cells

Associated with lymph node metastasis

VEGFR-3

Mediates the majority of VEGF angiogenic effectsVEGFR-2

Crucial to embryonic angiogenesis

Does not appear to be critical in pathogenic

angiogenesis

VEGFR-1

The The VEGFRsVEGFRs differ in their downstream signaling effectsdiffer in their downstream signaling effects

Effects mainly in lymphatic cellsVEGFR-3

Proliferation

Migration

Survival

Angiogenesis

VEGFR-2

Possible “decoy receptor” effect

Induction of other factors

VEGFR-1

EffectsReceptor

VEGF VEGF signalingsignaling

Angiogenic Angiogenic andand vasculoprotectivevasculoprotective functionsfunctions ofof VEGFVEGF

MechanismsMechanisms ofof antianti--apoptoticapoptotic VEGF VEGF signalingsignaling

Zachary, Cardiovasc Res 2001

Phosphotydyloinositol

3 kinase

Focal

adhesion

kinase

AKT = PKB

MechanismsMechanisms ofof chemotacticchemotactic VEGF VEGF signalingsignaling


Qiagen

MechanismsMechanisms ofof mitogenicmitogenic VEGF VEGF signalingsignaling


Extracellular signal-regulated kinases

Diacyloglicerol+

Inositol 1,4,5 -trisphosphate

Proteins with

src homology

(SH) 2 domain

phosphatydylinositol

4,5 biphosphate

Phospholipase C

VEGF VEGF levellevel hashas to be to be tightlytightly

regulatedregulated duringduring developmentdevelopment

andand postnatalpostnatal lifelife

Embryonic development is disrupted by modest

increase in VEGF gene expression

Miquerol L, Langille BL, Nagy A.Development, 2000: 127:3941-6

2-3 fold overexpression is deletorious to embryonic development

Enlarged hearts

Embryos died between E12.5 and E14.5

A A andand B. B. NoteNote prominent prominent tissuetissue edemaedema

andand newnew bloodblood vesselvessel formationformation. .

C. C. NoteNote alsoalso a prominent a prominent leakageleakage ofof

plasmaplasma protein protein complexescomplexes fromfrom

locallylocally hyperpermeablehyperpermeable earear vesselsvessels..

TooToo high high andand unbalancedunbalanced expressionexpression ofof VEGF VEGF

afterafter genegene deliverydelivery usingusing adenoviraladenoviral vectorsvectors

How to assess the role of different

VEGF isoforms, if the knockout of the

gene is lethal?

ConditionalConditional knockoutsknockouts ofof genesgenes

This strategy is based on a tissue-specific or conditionally-induced inactivation

of the gene of interest. This can be achieved by means of a Cre recombinase,

that catalyzes site-specific recombination of DNA between loxP sites.

A Cre recombinase is an enzyme that deletes the DNA fragment located

between the two recombinase-specific (LoxP) sites. A mouse bearing the

recombinase-specific sites (introduced by homologous recombination in

Embryonic Stem cells) is bred with a mouse expressing the recombinase

(generated by homologous recombination or transgenesis). The tissue-specific

expression of the recombinase allows the inactivation of the gene of interest

only in the tissue where the recombinase is expressed.

Transgenic animals, in which the target gene is flanked

by Lox sequences, must also express Cre recombinase

Thus, they have to be cross-bred with mice expressing

Cre. The expression of Cre can be:

1. Tissue specific – Cre gene is driven by the tissue

specific promoter, eg. heart, liver etc.

2. Conditionally induced – Cre gene is driven by the

inducible promoter, eg. tetracycline-induced or IFN-α

induced

CreCre--drivendriven conditionalconditional expressionexpression ofof genesgenes

Two independent approaches to inactivate the angiogenic protein

VEGF in newborn mice were employed:

1. inducible, CreloxP- mediated gene targeting

2. administration of mFlt(1-3)-IgG, a soluble VEGF receptor chimeric

protein.

Partial inhibition of VEGF achieved by inducible gene targeting

resulted in increased mortality, stunted body growth and

impaired organ development, most notably of the liver.

Administration of mFlt(1-3)-IgG, which achieves a higher degree of

VEGF inhibition, resulted in nearly complete growth arrest and

lethality.

VEGF is required for growth and survival in neonatal mice

Gerber et al., 1999

Gerber et al., 1999

VEGF VEGF isis requiredrequired for for growthgrowth andand survivalsurvival inin neonatalneonatal mice mice

One allele of VEGF

deleted in exon 3

VEGF VEGF isis requiredrequired for for growthgrowth andand survivalsurvival inin neonatalneonatal mice mice

1. 38% mortality at day 7 in mice without VEGF (its synthesis was

blocked from day 3);

2. Liver changes - smaller hepatocytes, immature sinusoids, increased

extramedullary hematopoiesis and almost complete absence of

Flk-1 positive endothelial cells;

3. Similar effects as after targeted knockouting of VEGF were obtained

when mice were treated with a soluble VEGF receptor chimeric protein.

Kidneys from mFlt(1-3)-IgG-treated animals weresmaller, had a granularsurface appearance andshowed punctuate areas

of hemorrhage.

Hearts from control andmFlt(1-3)-IgG-treated

animals: heartsfrom mFlt(1-3)-IgG-

treated animals weresignificantly smaller.

Gerber et al., 1999

TheThe effecteffect ofof differentdifferent

isoforms isoforms ofof VEGF on VEGF on

angiogenesisangiogenesis

VesselVessel formationformation andand sproutingsprouting angiogenesisangiogenesis inin

embronyicembronyic bodiesbodies inin responseresponse to to thethe differentdifferent VEGF isoformsVEGF isoforms

Formation of peripheral vascular plexus in two-dimensional EB cultures,

visualized by anti-CD31 immunostaining (red), was induced by 1 nmol/L

VEGF-A165, but not by VEGFA165b,VEGF-A121, VEGF-A145, or vehicle.

Kawamura et al. Cancer Res. 2008

VesselVessel formationformation andand sproutingsprouting angiogenesisangiogenesis inin

embryonicembryonic bodiesbodies inin responseresponse to to thethe differentdifferent VEGF VEGF ligandsligands

Vascularization of Matrigel plugs in nude mice. Plugs were fixed and stained to

detect CD31 on endothelial cell (red) and α-SMA (ASMA) on pericytes (green)

by immunofluorescent detection.


inclusion of VEGF-A165b led to invasion of endothelial cells

into the Matrigel, but the cells failed to organize into vessels

and also failed to attract pericytes

VEGF-A165bVEGF-A165b

endothelial cells pericytes


VEGF-A121VEGF-A121



In the VEGF-A121–containing Matrigel plugs, occasional

vessel structures were seen, which lacked branch

points and a pericyte coat

VEGF-A145VEGF-A145



In VEGF-A145–containing Matrigel plugs, branching,

pericyte-clad vessels were seen but to a much lesser extent

than in the VEGF-A165–containing Matrigel plugs

Inclusion of VEGF-A165 induced abundant vascularization of

the Matrigel with richly branched, pericyte-covered vessels



VEGF-A165VEGF-A165

!VEGF165 is the crucial isoform!

the role of single VEGF isoforms was studied in

retinal vascular development - mice selectively

expressing single isoforms were created

OrganisationOrganisation ofof mousemouse VEGF VEGF genegene

Exons 1-5 8

Exons 1-5 87

VEGF-A120

VEGF-A164

VEGF-A188Exons 1-5 876A1 A2

ImpairedImpaired retinalretinal vascularvascular developmentdevelopment

inin VEGFVEGF120/120120/120 andand VEGFVEGF188/188188/188 mice mice

Stalmans et al., JCI 2002

ArteriolarArteriolar andand venularvenular patterningpatterning inin retinasretinas ofof mice mice

selectivelyselectively expressingexpressing VEGF isoformsVEGF isoforms

The present study investigates

the distinct role of the different

VEGF isoforms in retinal vascular

development. Retinal vascular

development was normal in

VEGF164/164 mice. In contrast,

VEGF120/120 mice exhibited

severe vascular defects, with

impaired venous and severely

defective arterial vascular

development in the retina.

VEGF188/188 mice had normal

venous development, but aborted

arterial outgrowth.

Stalmans et al., JCI 2002

Site-specific removal of VEGF exons 6 and 7 in embryonic stem cells using the

Cre/LoxP system was achieved

The authors used targeted ES cells to generate VEGF+/120 mice, which seemed

normal and healthy.

Neonates expressing exclusively VEGF120 (VEGF120/120) were recovered at birth at

a normal Mendelian frequency: of 120 neonates, 26% were VEGF+/+, 51% were

VEGF+/120 and 24% were VEGF120/120.

About half the VEGF120/120 neonates died within a few hours after birth because of

bleeding in several organs

Dissection of VEGF120/120 mice showed they had enlarged hearts, irregular heart

beats and dysmorphic, weak heart contractions

EffectEffect ofof conditionalconditional knockoutknockout ofof VEGF164 VEGF164

andand VEGF188 on VEGF188 on myocardialmyocardial angiogenesisangiogenesis

CarmelietCarmeliet et al., 1999et al., 1999

Capillary density increases 300% in

VEGF+/+ hearts (filled bars) but not in

VEGF120/120 hearts (stippled bars).

There were fewer α-actin stained

coronary vessels per section in

VEGF120/120 hearts (stippled bars)

than in VEGF+/+ hearts (filled bars).

No difference in angiogenic potentials of various VEGF isoforms

VEGF121

VEGF165

controlcontrol

VEGF121

VEGF165

Matrigel assay Spheroid assay

Jozkowicz and Dulak

Actions of nitric oxide,

carbon monoxide and

hydrogen sulfide- toxic pollutants

or physiological regulators?

NitricNitric oxideoxide as a mediator as a mediator ofof VEGF VEGF signalingsignaling

Nitric oxide synthases

eNOS - endothelial (constitutive) NOS (NOS III) nNOS - neuronal (constitutive) NOS (NOS I)iNOS - inducible (NOS II)

L-arginine

O2

.NO

L-citrulline

NOS

cofactors

inhibitors of NOS isoforms

L- NAME - L-NG-Nitroarginine methyl ester

L-NMMA - L-NG-monomethyl arginine citrate


VEGF-induced signaling in endothelial cells

Dose-dependent NO release by HUVEC incubated with VEGF

Jozkowicz et al., Acta Biochim Pol, 1999

HUVEC proliferation induced by VEGF – dependence on NO



NO is a mediator of VEGF

InvolvementInvolvement ofof nitricnitric oxideoxide inin angiogenic angiogenic activitiesactivities ofof VEGF isoforms VEGF isoforms

Time [sec]

NO

co n

cen t

r ati o

n[ n

mo l

/L]

100

200

300

400

500

05 10 15 20 25 30

VEGF121

VEGF165

VEGF

Release of NO by VEGF-stimulatedendothelial cells is strongerin case of VEGF121 isoform

Józkowicz, Dulak et al., Growth Factor, 2004

0

2

4

6

8

10

12

14

16

control 121 121L-NAME

121

D-NAME

165 165L-NAME

165

D-NAME

cGM

P[fm

ol/m

l]

#

*

#

*

Synthesis of cGMP by VEGF-stimulatedendothelial cells is higher

in case of VEGF121 isoform

A. VEGF121 eNOS activity MigrationAssemblyCapillary sprouting

Proliferation

B. VEGF165 eNOS activityeNOS expression

MigrationAssembly

ProliferationCapillary sprouting

Properties of VEGF121 and VEGF165 isoforms

HH22S S –– maymay itit affectaffect angiogenesisangiogenesis??

H2S is generated endogenously in mammalian tissues

Hydrogen sulfide (H2S), a well known toxic gas, is generated endogenously inmammalian tissues from L-cysteine by pyridoxal-5’-phosphate-dependent enzymes, including

• cystathionine β-synthase (CBS)

• cystathionine γ-lyase (CSE),

• cysteine aminotransferase (CAT)

• cysteine lyase

The expression of H2S-generating enzymes is tissue specific.

• CBS is highly expressed in the hippocampus and cerebellum in the mammalianbrain

• CSE is predominant in the vasculature in both vascular smooth muscle cellsand endothelial cells

Angiogenesis begins fromlocal matrix degradation inpre-existing blood vessels, possibly induced by H2S.

Endothelial cell proliferationand migration and capillarysprout formation are activatedby H2S.

Newly formed capillaries mayfuse into bigger functionalvessels and H2S may be involved in this process.

Mechanisms of angiogenesis and

the effect of hydrogen sulfide

HH22S S

Hydrogen sulfide promotes angiogenesis in vitro

Wang et al., Clin Exp Pharmacol Physiol. 2010

Hydrogen sulfide promotes angiogenesis in vitro

Hydrogen sulfide promotes angiogenesis in vivo

Wang et al., Clin Exp Pharmacol Physiol. 2010

representative post-mortemangiograms after femoral arteryocclusion in the rat. There was more collateral vessel formation inthe ischaemic left hindlimb of ratstreated with 100 umol ⁄ kg per dayNaHS than in the control.

The arrows indicate the site ofligation of the femoral artery.The arrowhead indicates the typicalappearance of collateral vessels.

Hydrogen sulfide promotes angiogenesis in vivo

Changes in total burn wound area over time. Four animals for CSE wild-type group and five for CSE knockout mice were used.

Papapetropoulos et al., PNAS 2009

Heme Heme oxygenaseoxygenase pathwaypathway

Heme oxygenase

Ferritin

tissue injury

Hemeproteins

Fe2+ tissue injury

bilirubin protectionbiliverdin

CO

protection

soluble guanylyl cyclase

cGMPGTP

protection

Heme

p38

BvR

VEGF (VEGF-A) is a key mediator of vasculogenesis, angiogenesis

and arteriogenesis

TakeTake--homehome messagesmessages

VEGF is generated in the form of several isforms, being the results of alternative

splicing

The most common and the most active and crucial isoform is VEGF165

VEGF exerts its activity by binding to its receptors: VEGFR1, VEGFR2 and co-

receptors: neuropilin 1 & 2.

VEGFR2 is the key receptor, mediating the majority of actions of VEGF.

VEGFR1 is a decoy receptor, playing an important role in modulating VEGF

activity during development

NO, CO and H2S are important mediators in angiogenesis

wyklad 2 12 03 2012

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