ANGIOGENESIS Vasculogenesis: - PowerPoint Presentation

Slide1

ANGIOGENESIS

Vasculogenesis:

Embryonic development from endothelial precursors called ‘

angioblasts

’

Angiogenesis/ neovascularization:

Process of blood vessel formation in adults

By branching and extension of adjacent blood vessels and

Recruitment of EPCs from bone marrow.

This is Critical in chronic inflammation and fibrosis , tumor growth and vascularization of ischemic tissues.

Exploration of therapeutic potential of agents that are :

Pro-

angiogenic

(increase blood vessels)

Anti-

angiogenic

(Block pathologic angiogenesis)

Angiogenesis from Pre-Existing vessels:

Vasodilation in response to NO and VEGF

Proteolytic

degradation of BM of parent vessels by

metalloprotinases

and disruption of cell to cell contact between endothelial cells of vessels by plasminogen activators .

Migration of endothelial cells toward

angiogenic

sitmulus

.

Proliferation of endothelial cells behind leading front of migrating cells.

Maturation of endothelial cells which included inhibition of growth and remodeling into capillary tubes.

Recruitment of

peri

-endothelial cells. (

pericytes

and vascular smooth muscle cells. )

Angiogenesis from EPCs:

Embryonic development of hematopoietic and vascular systems have common precursor ‘

hemangioblast

’

Hematopoietic Stem cells

Angioblasts

.

Angioblast

like cells ‘EPCs’

Homing mechanism uncertain.

Express marker of both hematopoietic stem cells and endothelial specific.

Participate in replacement of lost endothelial cells,

reendothelization

of vascular implants, neovascularization of ischemic organs.

GROWTH FACTORS AND RECEPTORS INVOLVED IN ANGIOGENESIS:

VEGF

:

Secreted by many mesenchymal cells and stromal cells.

VEGFR-2, tyrosine kinase receptors restricted to endothelial cells.

VEGF Interaction and mobilization of EPCs  Angiogenesis VEGF  Pre-Existing local vessels  sprouting of new capillariesFGF2  Endothelial proliferation, differentiation and migration.

Vascular Endothelial Growth Factors (VEGF)

Proteins

Family members: VEGF (VEGF-A), VEGF-B, VEGF-C, VEGF-D

Dimeric

glycoprotein with multiple isoforms

Targeted mutations in VEGF result in defective vasculogenesis and angiogenesis.Production

Expressed at low levels in a variety of adult tissues and at higher levels in a few sites, such as podocytes in the glomerulus and cardiac myocytes

Inducing Agents

Hypoxia

TGF-β

PDGF

TGF-α

Receptors

VEGFR-1

VEGFR-2

VEGFR-3 (lymphatic endothelial cells)

Targeted mutations in the receptors result in lack of

vasculogenesis

Functions

Promotes angiogenesis

Increases vascular permeability

Stimulates endothelial cell migration

Stimulates endothelial cell proliferation

VEGF-C selectively induces hyperplasia of lymphatic vasculature

Up-regulates endothelial expression of plasminogen activator, plasminogen activator inhibitor 1,

and collagenase

Modulation of

Vasculogenisis

:

Notch pathway:

Promotes proper branching of new vessels and prevents excessive angiogenesis by decreasing responsiveness to VEGF.

Notch ligands and receptors are membrane bound molecules conserve in species. 5 notch ligands in mammals : jagged 1&2, delta like ligands (DLL) 1,3,4 4 trans-membrane receptors: Notch 1-4DLL4 is endothelial cells specific and is expressed in arteries and capillaries but not in veins.

Newly formed vessels are fragile, needs stabilization requiring pericytes

and smooth muscles cells.

Ang

1 and

Ang

2 , PDGF, TGF- β participate in stabilization process. Ang1  Tie 2; to recruit periendothelial cells. PDGF  recruit smooth muscles cellsTGF β  production of ECM proteins Physiologic and pathologic angiogenesis can be influences by agents or conditions that stimulates VEGF expression e.g. (TGF β, PDGF. TGF- α ) and tissue hypoxia.

ECM proteins as regulator of

angiogeneisis

:

Mortality and directed migration of endothelial cells is required for the formation of new-blood vessels. These processes are controlled by several classes of proteins.

Integrins

αv β3 – Multiple effects, Matricellular proteins - destabilize cells – matrix interactions and therefore promote angiogenesis. Proteinases and matrix metalloproteinases.

Endothelial Cells:

Endothelium:

Single cell thick continuous lining of the entire cardiovascular system. Its structure and function is vital for homeostasis and normal circulatory function. Endothelial cells can be identified,

immuno

histochemically with antibiodies to PECAM-I, CD34, vWF. Endothelium has many synthetic and metabolic properties.

MAINTENANCE OF PERMEABILITY BARRIER

ELABORATION OF ANTICOAGULANT, ANTITHROMBOTIC, FIBRINOLYTIC REGULATORS

Prostacyclin

Thrombomodulin

Heparin-like molecules Plasminogen activator

ELABORATION OF PROTHROMBOTIC MOLECULES

Von

Willebrand's

factor

Tissue factor

Plasminogen

activator inhibitor

EXTRACELLULAR MATRIX PRODUCTION (COLLAGEN, PROTEOGLYCANS)

MODULATION OF BLOOD FLOW AND VASCULAR REACTIVITY

Vasconstrictors: endothelin, ACE Vasodilators: NO, prostacyclin REGULATION OF INFLAMMATION AND IMMUNITY IL-1, IL-6, chemokines Adhesion molecules: VCAM-1, ICAM, E-selectin, P-selectin Histocompatibility antigens REGULATION OF CELL GROWTH Growth stimulators: PDGF, CSF, FGF Growth inhibitors: heparin, TGF-β OXIDATION OF LDL

ENDOTHELIAL CELLS PROPERTIES AND FUCNTIONS

Semipermeable.

Vascular endothelium has phenotypic variations.

Large vessels and

capilaries

Arteries and veins

Lymphatics Structurally endothelial cell can respond to pathophysiological stimuli “Endothelium activation”

Age related Macular degeneration

Advancing age is a risk factor.

71% heritable, CFH (Complement factors H) CC genotype.

Structural and functional unit:

RPE,

Bruch membrane, Choroidal vasculature

Disturbance in any component of unit affect health of overlying photoreceptors producing visual loss.

ARMD:

Atrophic or dry,

Neovascular

or wet/exudative.

Choroidal neovascularization:

Presence of

angiogenic

vessels presumably originate from

choriocapillaris and penetrate through the Bruck’s membrane beneath the RPE or penetrate RPE become situated beneath the neurosensory retina. These vessels leaks, excude, haemorrhage  vitreous hemorrhage. Neovascular ARMD → VEGF antagonists into vitreous of the effected eye.Choroidal neovascular membrane also seen in- pathologic myopia, trauma to bruck’s membrane, angiods streaks, immunological response to systemic histoplasmosis.