vasculogenesis and arteriogenesis angiopoietins , ephrins...

Vasculogenesis Vasculogenesis andand ArteriogenesisArteriogenesis

AngiopoietinsAngiopoietins, , ephrinsephrins andand othersothers

lecture VIII

30th April 2012

EC – endothelial cell

P – pericyte

F – fibroblast

VEGF – vascular endothelial

growth factor

PDGF – platelet-derived

growth factor

Ang-1 – angiopoetin-1

Mechanisms of new blood vessels formationMechanisms of new blood vessels formation

Vasculogenesis

EC

P

Endothelial

Progenitor

Cell

Capillary

blood vessel

Angiogenesis

EC

P

EC

EC

P

EC

P

Capillary

blood vessel Network of capillaries

VEGF

Arteriogenesis

EC

P

EC

SMCSMC

SMCSMC

F

F

Primary

blood vesselMature artery

increased blood flow

VEGF + PDGF

VEGF + Ang-1

Vasculogenesis Vasculogenesis

Vasculogenesis begins very early after the initiation of

gastrulation in the mammalian embryo, with the formation

of the blood islands in the yolk sac and angioblast

precursors in the head mesenchyme

capillaries are formed from

vascular progenitor cells

VasculogenesisVasculogenesis

1. First phase

• Initiated from the generation of hemangioblasts;

2. Second phase

• Angioblasts proliferate and differentiate into

endothelial cells

3. Third phase

• Endothelial cells form primary capillary plexus

In the yolk sac, these progenitors aggregate into endothelial-lined blood islands that

then fuse to generate a primary capillary plexus. The primary capillary plexus

undergoes remodelling along with intra-embryonic vessels to form a mature circulation

Hemangioblast is a multipotent cell, common precursor to

hematopoietic and endothelial cells. Hemangioblast was first

hypothesized in 1900 by Wilhelm His.

HemangioblastHemangioblast

Vasculogenesis Vasculogenesis inin adultadult

Vasculogenesis Vasculogenesis occursoccurs alsoalso inin adultadult organismorganism

Previously, postnatal vascularization was thought to occur exclusively due to

angiogenesis. However, recent investigations have shown that vasculogenesis is

involved in blood vessel formation also during postnatal live and the cells

responsible for that are EPCs.

JCI 1999;103:1231-1236

• Classic Paradigm:

Angiogenesis– Mature ECs migrate and

proliferate to form new vessels

• New Model: Angiogenesis +

Vasculogenesis

– Bone Marrow derived EPCs circulate to sites of neovascularization

MechanismsMechanisms ofof EPCsEPCs hominghoming andand differentiationdifferentiation

Urbich & Dimmeler, Circ Res 2004

Endothelial progenitor cells

A primitive cell made in the bone marrow (or other

organs) that can enter the bloodstream and go to areas

of blood-vessel injury to help repair the damage

Endothelial Progenitor CellsEndothelial Progenitor Cells

DiIDiI AcLDLAcLDL uptakeuptake

EPC

1:200 2h

Anna Anna GrochotGrochot--PrzeczekPrzeczek

IsolectinIsolectin bindingbinding by EPC by EPC

control

isolectin

Lectin from Bandeira simplicifolia

Anna Grochot-Przeczek

ImmunohistochemicalImmunohistochemical characterisationcharacterisation ofof

cultureculture--expandedexpanded EPCsEPCs

Cytoplasmic factor VIII

(von Willebrand factor)

Uptake

of acetylated

low density

lipoproteins

2 weeks

culture

tube formation

on Matrigel

Dzau et al., Hypertension 2005,

MarkersMarkers ofof endothelialendothelial progenitorprogenitor cellscells

CD34

VEGFR2

CD133 (prominin, AC133)

CD133 is absent on mature endothelial cells and monocytic cells

• a powerful mechanism to ensure blood supply to tissue at risk if

a main artery is chronically occluded

• refers to an increase in the diameter of existing arterial vessels

mechanical stimulation chemical stimulation

elevated blood pressure and

increased blood flow

upregulation of cytokines

and cell adhesion receptors

VEGF, MCP-1, TNF-α, bFGF,

MMP, angiopoietins,

fluid shear stress is induced

by the altered blood flow conditions

after an arterial occlusion –

shear stress is a force of the flowing blood on the

endothelial surface of the blood vessel

ArteriogenesisArteriogenesis

Van Royen et al., Cardiovasc Res 2001

DifferencesDifferences BetweenBetween

AngiogenesisAngiogenesis andand ArteriogenesisArteriogenesis

AbleUnableCompensation for

an occluded artery

10- to 20-fold1.5- to 1.7-foldIncreases blood flow

maximally

Inflammation because of

increased shear stress

Inflammation because of

ischemic focal tissue damage

Cellular mechanism

Shear stressIschemiaTrigger

Pre-existing arteriolesPre-existing capillariesSource

Growth of collateral

arteries

Formation of new capillaries

by sprouting

Definition

ArteriogenesisAngiogenesis

ArteriogenesisArteriogenesis -- collateralcollateral circulationcirculation

This is a process in which small (normally closed)

arteries open up and connect two larger arteries or

different parts of the same artery.

They can serve as alternate routes of blood supply.

Collateral vessels (arteriogenesis) can develop

around the site of coronary occlusion

(a) remodelling of pre-existing

vessels that gradually

enlarge to the point at which

they can carry the bulk of

blood flow

budding of new vessels from

post-capillary venules on the

adventitial surface of the

occluded artery that

gradually expand and

connect to the distal arterial

segment.

Growth of collateral blood vessels (arteriogenesis) is potentially

able to preserve structure and function of organs after

occlusion of a major artery.

The remodeling process depends on the following conditions:

(1) existence of an arteriolar network that connects the preocclusive with

the postocclusive microcirculation;

(2) activation of the arteriolar endothelium by elevated fluid shear stress;

(3) invasion (but not incorporation) of bone marrow–derived cells

(4) proliferation of endothelial and smooth muscle cells.

1. The initial triggers of arteriogenesis are physical forces like

fluid shear stress

2. Attraction and invasion of circulating blood cells – monocytes

3. Proliferation of vascular wall cells

4. Remodeling processes with digestion and rearrangement of

the extracellular matrix and elastic lamina.

ArteriogenesisArteriogenesis –– stepssteps

Waltenberger 2001, Circulation

ArteriogenesisArteriogenesis inin collateralcollateral developmentdevelopment –– involvementinvolvement ofof

endothelialendothelial cellscells, , smoothsmooth musclemuscle cellscells andand monocytesmonocytes

ArteriogenesisArteriogenesis –– stepssteps

This series of electron microscopic figures shows subsequent steps of

the collateral vessel wall invasion by blood monocytes

HeilHeil, , SchaperSchaper CircCirc ResRes 20042004

Monocytes in collateral artery growth

Role Role ofof VEGFRVEGFR--1 1 inin arteriogenesisarteriogenesis ––

stimulationstimulation ofof monocytemonocyte migrationmigration

Waltenberger 2001, Circulation

PlGF

VEGF VEGF familyfamily

Integrins E, P selectin VEGFR-1 VEGFR-2 TIE-2 TIE-1

sVEGFR NRP-1 VEGFR-3

ephrins

IgG superfamily

(VCAM-1, ICAM-1)

Ang1

Ang2

Ang3

Ang4

B1 A1 B2

B2 B3 B4 A2

ephrin receptors

A B C D E PlGF

VEGF

?

+

-

-

+

DiversityDiversity ofof angiogenic angiogenic factorsfactors//receptorsreceptors

Jain and Munn Nature Med. 2000, modified

Carmeliet, 2005; Semenza 2003

BloodBlood vesselvessel formationformation –– variousvarious waysways

Yancopoulos, Science 2000

Receptorson endothelial

cells

TwoTwo classesclasses ofof endothelialendothelial cellcell specificspecific tyrosinetyrosine kinasekinase receptorsreceptors

Jones N et al., Jones N et al., NatureNature CellCell BiolBiol 20012001

Ig-like domain

EGF-like

cysteine repeats

Fibronectin type III

homology domains

Tyrosine kinase domain

TieTie--1 1 andand TieTie--2 2 receptorsreceptors

1. Endothelial cell specific tyrosine kinase receptors

2. Built of extracellular and intracellular domains – different than

VEGF receptors

3. Expressed early in development, especially in endothelial cells

4. Tie-1/Tie-2 – specific markers of EC, are also present on

certain hematopoietic cell types

5. Tie –2 - receptor for angiopoietins

Tie –1 - ?

KnockoutsKnockouts ofof TieTie--1 1 andand TieTie--2 2 receptorsreceptors

Tie-1 -/- die between E13.5 and E18.5

normal development up to E13.0; then local hemorrhage,

edema, rupture of microvessels

Tie-2 -/- die at E10.5

cardiac failure, hemorrhage, other vascular defects

embryos have low number of endothelial cells, lack of smooth

muscle cells

69% 63%

AngAng--11

AngAng--22

coiled-coil domain fibrinogen-like domain

responsible for

oligolimerization pattern

mediates

receptor phosphorylation

C

C

N

N

44%

42% 55%

57% AngAng--33

AngAng--44C

C

N

N

AngiopoietinsAngiopoietins

AngAng--1 1

1. Ligand for Tie-2

2. Does not induce endothelial cell proliferation, but is required

for their survival

3. Expressed in the myocardium and perivascular cells

4. Ang-1-/- - defects similar to Tie-2-/-

- death of embryos at E12.5,

- lack of stabilization and remodelling of vessels – lack of the

interaction between endothelial and supporting cells

AngAng--1 1 activitiesactivities

• is responsible for sprouting angiogenesis (like VEGF) but Ang-1 is a weak

mitogen for endothelial cells

• gene knockout studies have demonstrated that VEGF is necessary for the

formation of the initial vascular plexus during embryogenesis, whereas Ang-1 is

essential for subsequent remodeling, maturation and stabilization of vessels

• the mechanism of Ang-1 on migration, tube formation and

survival of endothelial cells in vitro is mediated via PI3K and

downstream effectors of the cascade

• overexpression of Ang-1 leads to strong vasculature, probably

due to the promotion of remodeling and inhibition of pruning

AngAng--1 1 activitiesactivities

Central role Central role ofof Akt Akt kinasekinase inin angiogenesisangiogenesis signalingsignaling

Dimmeler & Zeiher, Circ Res 2000

EndothelialEndothelial cellcell apoptosisapoptosis andand AngAng--11

p85, p110 – subunits of PI3K

Overexpression of Ang-1 in the

skin of transgenic mice

IncreasedIncreased Vascularization in Vascularization in MiceMice

OverexpressingOverexpressing AngiopoietinAngiopoietin--1 1

Suri et al, Science 1998

skin phenotype

in newborn

Skin phenotype in adult Ang1 transgenic mice –

big differences

IncreasedIncreased Vascularization in Vascularization in MiceMice

OverexpressingOverexpressing AngiopoietinAngiopoietin--1 1

Suri et al, Science 1998

Ang-1 exerts effects which areopposite to VEGF action

• in contrast to VEGF, which is one of the strongest vascular permeability factor, Ang-1 decreases vessels permeability. In this way Ang-1 can protect blood vessels from the VEGF activity and connected tissue edemas

• Ang-1 overexpression may have also an anti-inflammatory effect. VEGF stimulates endothelium to produce tissue factor and induces inter-cellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1(VCAM-1) and E-selectin expression which leads to the adhesion of leukocytes. Ang-1 may protect from these harmful effects of VEGF.

Ang-1 has anti-permeability &

anti-inflammatory functions

VEGF

vascular permeability factor (VPF)

VCAM-1 ICAM-1 E-selectin

adhesion of leukocytes

Thurston et al., Nature Med. 2000

StrongStrong VEGF VEGF expressionexpression inducesinduces massivemassive edemaedema ––

VEGF VEGF isis alsoalso a a vascularvascular permeabilitypermeability factorfactor

massive edema in four organs

36 h after intravenous

administration of AdVEGF

Thurston et al., Science 1999

Comparison of untreated ear skin of wild-type, K14-VEGF and K14-Ang1 mice

The skin of K14-VEGF

mice was redder than

normal, but, unlike the

skin of K14-Ang1 mice, it

was also thicker than

normal, with regions of

increased cellularity and

foci of inflammatory cells.

Leakage-resistant blood vessels

in mice overexpressing Ang-1


increase in

vessel length

increase in

vessel diameter

LeakageLeakage--resistantresistant bloodblood vesselsvessels inin mice mice overexpressingoverexpressing AngAng--11


ComparisonComparison ofof plasmaplasma leakageleakage inin earear skinskin

afterafter treatmenttreatment withwith inflammatoryinflammatory agentsagents

mustard oil - an inflammatory

agent that induces plasma

leakage and inflammation

in the skin

Evans blue dye to

visualize leakage

Thurston et al., Nature Med. 2000

SystemicSystemic AngAng--1 1 productionproduction by by adenoviraladenoviral genegene

deliverydelivery causescauses resistanceresistance to to vascularvascular leakageleakage

Ears of mice treated with

Ad–Ang1 or Ad–GFP and,

3 d later, injected

intravenously with Evans

blue dye to visualize

plasma leakage, followed

by exposure to saline or

mustard oil for 30 min.

• viral overexpression of Ang-1 increases lymphangiogenesis in

mouse skin and cornea

• influence of Ang-1 on lymphangiogenesis is connected with

upregulation of VEGFR-3

Thus, similarly to Ang-1 and VEGF cooperation in blood vessel

development, crosstalk with VEGF-C and D during formation of

lymph vessels can occur

AngAng--1 1 inin lymphangiogenesislymphangiogenesis

Formation of filopodia and

endothelial sprouts was observed

already 2 days after adenoviral

delivery of Ang1 and VEGF-C

At 4 days, the sprouting and

endothelial activation increased

in the Ang1-treated and VEGF-C

ears

After 14 days, both Ang1- and

VEGF-C–treated samples showed

vessel network formation and

stabilization of the lymphatic

endothelium

AngiopoietinAngiopoietin--1 1 promotespromotes lymphaticlymphatic

sproutingsprouting andand hyperplasiahyperplasia

Tammela et al.. Blood 2005

Thurston F, Cell Tissue Res 2003

AngiopoietinAngiopoietin--22

1. Ligand for Tie-2 - antagonist of Ang-1 in some cells

- but in others – can phosphorylate Tie-2

2. Expressed at low level by endothelial cells, but is strongly

upregulated at sites of active vascular remodeling - ovary,

tumors

3. Is upregulated at times of both vessel growth and regression

– thus Ang-2 plays an active role in blood vessel remodeling

4. Ang-2 -/- - born relatively normal, but many die at 14 day –

defects in remodeling of the vessels

5. Transgenic overexpression of Ang-2 disrupts blood vessel

formation

Ang-2-deficient mice are born apparently normal - the functionally

unaffected blood vascular system of Ang-2-deficient mice has only

minor abnormalities

In contrast to the mild phenotype of Ang-2-deficient mice, mice

transgenically overexpressing Ang-2 have an embryonic lethal

phenotype that essentially phenocopies the Ang-1-null and Tie-2-

null phenotypes

The similarity of the Ang-1 loss-of-function phenotype with the Ang-2 gain-of-

function phenotype strongly supports the antagonistic concept of Ang-1 and Ang-2

functions

ExpressionExpression ofof AngAng--1 1 andand AngAng--2 2 inin variousvarious tissuestissues

AngiopoietinAngiopoietin--22

• Ang-2 is an antagonist of Tie-2 receptor- it binds to Tie-2 without inducing signal transduction in Tie-2-expressing

endothelial cells

- it antagonizes the binding of Ang-1 to the Tie-2 receptor

• its action is dependent on the VEGF expression

high VEGF level

Ang-2 cooperates with VEGF

enhancement of

angiogenesis

absence of VEGF

blood vessels remodeling

Ang-2 is upregulated in sites of

vessels regression

AngAng--2 2 andand VEGFVEGF

TieTie--2 ligand Angiopoietin2 ligand Angiopoietin--2 2

destabilizesdestabilizes quiescentquiescent endotheliumendothelium

HUVECs - human umbilical-vein endothelial cells

HUASMCs - human umbilical artery smooth-muscle cells

A-422885.66 - the low-molecular-weight Tie-2 inhibitor

Three dimensional co-culture model of endothelial cells and smooth-muscle

cells was used. In this model, smooth-muscle cells form the core of a spheroid

that is covered by a monolayer of endothelial cells. The surface endothelial

monolayer can be visualized by whole-mount CD31 or ICAM-1

immunocytochemistry

Scharpfenecker M et al. J Cell Sci 2005

Scharpfenecker, M. et al. J Cell Sci 2005

Induction of endothelialInduction of endothelial--cell detachment from endothelialcell detachment from endothelial--cell/smoothcell/smooth--

musclemuscle--cell cocell co--culture spheroids by pharmacological Tieculture spheroids by pharmacological Tie--2 inhibition2 inhibition

Scharpfenecker, M. et al. J Cell Sci 2005

Time course of AngTime course of Ang--22--mediated endothelialmediated endothelial--cellcell--monolayer monolayer

destabilization in HUVEC/HUASMC codestabilization in HUVEC/HUASMC co--culture spheroidsculture spheroids

Early development Late development & Adult

VEGF endothelial cells Ang1 vessel maturation

differentiation (agonist) & stabilization

proliferation

tube formation

Ang2(antagonist)

vessel de-stabilization

+ VEGF No VEGF

Adult neovascularization Vessel regression

AngAng--3 3 andand AngAng--44

• they bind to Tie2 receptor

• in experiments with human endothelial

cell lines, Ang3 was identified as an

antagonist of Tie2 and Ang4 was found to be

an agonist of Tie2

Ang4, but not Ang3, strongly induces Tie2 and

Akt phosphorylations in HUVECs

Lee et al., FASEB Journal

mouse Ang3 and human Ang4 were used

Ang3 is more potent than Ang4 in Akt phosphorylation and

survival in primary cultured mouse ECs

Both Ang3 and Ang4 induce strong angiogenesis in vivo

angiogenesis in the mouse corneal micropocket assay


Model for the action of Ang3 and Ang4 in human Tie2 and mouse Tie2. Ang4 is a

relatively potent agonist whereas Ang3 is a very weak agonist to human Tie2.

In comparison, Ang3 is a relatively potent agonist whereas Ang4

is a moderate agonist to mouse Tie2.




ephrins

IgG superfamily

(VCAM-1, ICAM-1)

Ang1

Ang2

Ang3

Ang4

B1 A1 B2

B2 B3 B4 A2

ephrin receptors

A B C D E PlGF

VEGF

?

+

-

-

+



EphrinsEphrins andand EphEph receptorsreceptors

Eph receptor tyrosine kinase family and their ligands,

ephrins, are critical regulators of vascular remodeling during

embryogenesis and in tumor neovascularization

• ephrins (Eph family receptor interacting proteins)

• the Eph receptors family (Erythropoietin-producing human

hepatocellular carcinoma) is the largest known family of receptor

tyrosine kinases consisting of 16 members

• both Eph receptors and their ligands are divided in two

subfamily – A and B

• ligands of EphrinA class are glycosylphosphatidylinisotol (GPI)-

anchored peripheral membrane molecules, whereas ephrinB

subfamily is formed by transmembrane proteins with cytoplasmic

domain

EphrinEphrin receptorsreceptors andand ephrinephrin ligandsligands

Augustin & Reiss, Cell Tissue Res, 2003

Yancopoulos, Science 2000

Receptors

on endothelial

cells

Eph receptors are present in high degrees during vasculogenesis

and early development of the circulatory system

They play a role in

- distinguishing between arterial and venous endothelium

- stimulation of the production of capillary sprouts

- differentiation of mesenchyme into perivascular support cells

Role Role ofof ephrinephrin//EphEph receptorsreceptors inin angiogenesisangiogenesis

Ephrin B2 – an early marker of arterial endothelial cells

EphB4 – marks venous endothelial cells

EphrinsEphrins andand EphEph receptorsreceptors ––

markersmarkers ofof arterioarterio--venousvenous identityidentity

EphrinB2 -/- - lethal at E10.5

Significant defects in vessels remodeling and sprouting

EphB4 -/- – also die at E10.5

BloodBlood vesselvessel defectsdefects inin ephrinB2 ephrinB2

nullnull mutant mutant embryosembryos andand yolkyolk sacssacs

growth retardation in ephrinB2

null mutant embryos

the normal formation of blood islands and

primary capillary plexus in wild-type, but

failure of angiogenic remodelling into larger

vessels in the mutant yolk sac

Mesoderm formation

Vascular DevelopmentVascular Development

Karkkarnin et al., 2002 Nature Cell Biology

Vasculogenesis

Lymphangiogenesis

Angiogenesis

Hemangioblasts

Blood island formation

Endothelial cells

Hematopoietic

cells

Primary vascular

plexus

Lymphatics

Lymphangioblasts

Capillaries

VE-Cadherin

bFGF

VEGF A

VEGFR-1/2/3

TGFb

EphrinB2/EphB4

Endoglin Notch

Ang1/2

Tie2

PDGF B

Id1/3

VEGF C/D

VEGFR-3

VEGF A

VEGFR-2

TGFb

Notch on Notch off

Notch is a large transmembrane receptor that is important for normal neurogenesis, somite

formation and lymphoid cell development. It plays a special role in blood vessel development.

VEGF-A

Notch1,4 Dll4

Hey1,2

EphB4 ephrinB2

Venous

EC

Arterial

EC

Venous/Arterial

Specification

CrossCross--talk talk betweenbetween ephrinBephrinB--EphB4 EphB4 andand VEGF/Ang1VEGF/Ang1

VEGF Ang1

PI3K kinase

Akt

EC survival

MAPK

EC proliferation

EphrinEphrin B2B2

Arterial EC

Evidence for Importance of Notch in Evidence for Importance of Notch in

Regulating Vascular FormationRegulating Vascular Formation

Notch -/- mouse embryo: primary plexus is

formed but there is lack of large and small vessels

Ephrins/Eph in tumors

• Overexpression of Eph receptors has been detected in different

types of solid tumors

• First evidence come from 1987 when EphA1 was found to be

more than 10-fold overexpressed in human hepatocellular

carcinoma cell line

• EphA1 was found to be expressed also in liver, lung, breast and

colon carcinoma

• EphA2 is upregulated in ovarian, lung, liver, gastrointestinal,

prostate cancers as well as melanomas and glioblastoma

• The expression of other members of the Eph receptors and also

ephrins is increased in a number of cancers and tumor cell lines



ephrins

IgG superfamily

(VCAM-1, ICAM-1)

Ang1

Ang2

Ang3

Ang4

B1 A1 B2

B2 B3 B4 A2

ephrin receptors

A B C D E PlGF

VEGF

?

+

-

-

+



VE-cadherin

• Vascular Endothelial-cadherin (VE-cadherin) is a calcium-

dependent cell-cell adhesion glycoprotein built of five

extracellular cadherin repeats, a transmembrane region and a

highly conserved cytoplasmic tail

• VE-cadherin interacts with α-, β- and γ-catenin

• VE-cadherin can signal with VEGFR-2 to mediate PI3K/Akt-

dependent endothelial cell survival

Role Role ofof VEVE--cadherincadherin inin angiogenesisangiogenesis

VE-cadherin and angiogenesis

Jones et al., Nature Rev 2001

VEVE--cadherincadherin isis indispensableindispensable for for

properproper vascularvascular developmentdevelopment

Gory-Fauré et al. Development 1999

mutant embryogrowth retardation, anemia,

pericardial hypertrophy and

incomplete folding.

External appearance of E10.5 yolk sacs. Blood

islands of the homozygous mutants remained

isolated (B,D), as opposed to the organized

vasculature of the wild type (A,C).

Role Role ofof VEVE--cadherincadherin inin angiogenesisangiogenesis

Disruption of VE-cadherin impairs angiogenesis – knockouts die at E9.5

Deficiency of VE-cadherin blocked the capacity of endothelial cells to respond to

survival signals induced by VEGF-A, by preventing formation of a complex

consisting of VE-cadherin, β-catenin, PI3-K, and VEGF receptor-2 (VEGFR-2)

Carmeliet et al., Cell 1999

AKT

survival

VE-cadherin VEGF-A

VEGFR2

PI3-Kβ-cat



ephrins

IgG superfamily

(VCAM-1, ICAM-1)

Ang1

Ang2

Ang3

Ang4

B1 A1 B2

B2 B3 B4 A2

ephrin receptors

A B C D E PlGF

VEGF

?

+

-

-

+



VascularVascular integrinsintegrins

A large number of vascular cell surface glycoproteins that function as

cell adhesion receptors to extracellular matrix and in cell-cell adhesion

Stupack and Cheresh, Science STKE, 2002

IntegrinsIntegrins

ProPro-- andand antianti--angiogenicangiogenic role role ofof ααvvββ33 integrinintegrin

• Vitaxin is in Phase II trial for colorectal cancer

• a humanized version of the antiangiogenic antibody LM609 directed against a

conformational epitope of the αvβ3 integrin complex

Vitaxin

• a promising angiogenesis inhibitor used in the treatment of some forms of

cancer

Abegrin

• Abegrin is a monoclonal antibody to human integrin αVβ3, a cell adhesion

molecule highly expressed on actively angiogenic endothelium and glioblastoma

multiforme tumor cells

AntiAnti--angiogenicangiogenic factorsfactors directeddirected againstagainst integrinsintegrins

LMLM--609; 609; VitaxinVitaxin 22, , ααvvββ33 antibodiesantibodies

Mice harboring either M21 (A) or A375 (B) melanoma xenografts were treated with 10

mg/kg Abegrin™ delivered thrice weekly starting on day 1 following tumor implantation.

M21 A375

Mulgrev, Mol Cancer Ther. 2006

AbegrinAbegrin™™ inhibitsinhibits humanhuman melanoma melanoma

tumor tumor cellcell growthgrowth inin vivovivo

Summary of the mechanisms of angiogenesis

arterio/

venous

differentiation

(ephrins/Eph)

TakeTake homehome messagesmessages

• Arteriogenesis is the third way of blood vessels formation

stimulated by elevated shear stress

• Ang1 and Ang2 act via Tie-2 receptor, but Ang-1 is an agonist

whereas Ang-2 antagonist of the receptor

• Ang-1 protects from increased permeability

• Ephrin/Eph receptors are markers of arterio-venous identity

• Adhesion molecules (VE-cadherin, integrins) play important

role in angiogenesis

vasculogenesis and arteriogenesis angiopoietins , ephrins...

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