2.18 - Angiogenesis in Scar Formation

Angiogenesis is the formation of new blood vessels from exiting vessels.

angiogenesis

development of new blood vessels from existing vessels

• involves mostly venules

• occurs through coordinated sequence

steps in angiogenesis

1. vasodilation → mediated by NO

   • more blood flow supports the developing tissue

2. increased vascular permeability → driven by VEGF

3. separation of pericytes from abluminal surface

   • pericytes function as contractile cells on vessels of small caliber

   • detach so endothelial cells can begin sprouting

4. endothelial migration towards area of injury

5. endothelial proliferation behind migrating cells

6. capillary tube formation → cells organize into vascular tubes/lumens

7. recruitment of pericytes for capillaries and smooth muscle cells for larger vessels

8. suppression of endothelial proliferation of migration

9. deposition of basement membrane → create organized ECM

VEGF

major angiogenesis molecule in injury and tumors, usually referring to VEGF-A

• expressed in most adult tissues

• bind to tyrosine kinase receptors on target cells (mainly endothelium)

• induced by hypoxia, PDGF, TGF-⍺, TGF-β

• functions —

  • initiates sprouting of endothelial cells by stimulating migration and proliferation

  • stimulates production of NO to promote vasodilation

  • contributes to formation of vascular lumen

• therapeutics — antibodies to VEGF developed

  • example — used for treatment of certain tumors that require angiogenesis for survival

fibroblast growth factors (FGFs)

family of growth factors, with FGF-2 most commonly involved in angiogenesis

• produced by many cell types

• binds surface tyrosine kinase receptors on target cells

  • can bind heparan sulfate for storage in ECM

• functions —

  • stimulates proliferation of endothelial cells

  • promotes migration of macrophages and fibroblasts to areas of injury

angiopoietins

angiopoietins 1 and 2 (Ang1, Ang 2) stabilize and mature vessels

• functions —

  • recruit pericytes and smooth muscle cells

  • deposit connective tissue

PDGF

recruits smooth muscle cells

• important during fibroblast proliferation and scar formation

TGF-β

suppresses endothelial proliferation and migration, and enhances ECM components

• stabilizes/finishes repair

integrins

ECM proteins that aid sprouting process through interaction with integrin receptors on endothelial cells

matrix metalloproteinases (MMPs)

degrade ECM to permit remodeling and extension of new vessels through matrix