Healing of skin wounds can be classified into healing by first intention (primary union), referring to epithelial regeneration with minimal scarring, as in well-apposed surgical incisions, and healing by second intention (secondary union), referring to larger wounds that heal by a combination of regeneration and scarring. Because the fundamental processes involved in both types of wound healing represent a continuum from regeneration to scarring, we do not make this distinction in our discussion of the key events in tissue repair.
Angiogenesis is the process of new blood vessel development from existing vessels. It is critical in healing at sites of injury, in the development of collateral circulations at sites of ischemia, and in allowing tumors to increase in size beyond the constraints of their original blood supply. Much work has been done to understand the mechanisms of angiogenesis, and therapies have been developed either to augment the process (e.g., to improve blood flow to a heart ravaged by coronary atherosclerosis) or to inhibit it (to frustrate tumor growth or block pathologic vessel growth, as in wet macular degeneration of the eye).
Angiogenesis involves sprouting of new vessels from existing ones, and consists of the following steps (
Fig. 3.25
Vasodilation in response to NO and increased permeability induced by VEGF
Separation of pericytes from the abluminal surface and breakdown of the basement membrane to allow formation of a vessel sprout
Migration of endothelial cells toward the area of tissue injury
Proliferation of endothelial cells just behind the leading front (“tip”) of migrating cells
Recruitment of periendothelial cells (pericytes for small capillaries and smooth muscle cells for larger vessels) to form the mature vessel
Suppression of endothelial proliferation and migration and deposition of the basement membrane
It has been suggested that endothelial progenitor cells are present in the bone marrow and can be recruited to promote new vessel formation. However, these cells likely play a minor, if any, role in the angiogenesis associated with the healing of most wounds.
Leading (”tip”) cell (VEGF, Notch
Formation of new vessel ECM Pericyte recruitment Elongation of vascular stalk
Fig. 3.25 Angiogenesis. In tissue repair, angiogenesis occurs mainly by the sprouting of new vessels. The steps in the process, and the major signals involved, are illustrated.The newly formed vessel joins up with other vessels (not shown) to form the new vascular bed.
The process of angiogenesis involves several signaling pathways, cell–cell interactions, ECM proteins, and tissue enzymes.
• Growth factors. VEGFs, mainly VEGF-A (Chapter 1), stimulates both migration and proliferation of endothelial cells, thus initiating the process of capillary sprouting in angiogenesis. It promotes vasodilation by stimulating the production of NO and contributes to the formation of the vascular lumen. Fibroblast growth factors (FGFs), mainly FGF-2, stimulate the proliferation of endothelial cells. They also promote the migration of macrophages and fibroblasts to the damaged area, and stimulate epithelial cell migration to cover epidermal wounds. Newly formed vessels need to be stabilized by the recruitment of pericytes and smooth muscle cells and by the deposition of connective tissue. Multiple growth factors, including PDGF and TGF-β, likely participate in the stabilization process: PDGF recruits smooth muscle cells and TGF-β suppresses endothelial proliferation and migration, and enhances the production of ECM proteins.
Notch signaling. Through “cross talk” with VEGF, the Notch signaling pathway regulates the sprouting and branching of new vessels and thus ensures that the new vessels that are formed have the proper spacing to effectively supply the healing tissue with blood.
ECM proteins participate in the process of vessel sprouting in angiogenesis, largely through interactions with integrin receptors of endothelial cells and by providing the scaffold for vessel growth.