Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 660

10.7.2 Angiogenesis Inhibition

Most body tissues are irrigated by blood vessels, except cartilage, tendons, liga-
ments, retina, and cardiac valves. The avascularity of these tissues is needed for an
appropriate functioning.
Excessive angiogenesis occurs in various diseases, such as cancer, macular
degeneration, diabetic retinopathy, rheumatoid arthritis, atherosclerosis, diabetic
nephropathy, pathologic obesity, asthma, cystic fibrosis, inflammatory bowel dis-
ease, psoriasis, endometriosis, vasculitis, etc. Aberrant angiogenesis in the cartilage
contributes to arthritis. Angiogenesis could be involved in degenerative tendon
and ligament diseases. Angiogenesis in the retina is associated with vision loss.
The cornea expresses soluble VEGFR1 (VEGFR1 S ), which binds to and se-
questers corneal VEGFa, inhibiting its activity even during hypoxia [ 1340 ]. 80 In
atherosclerosis, rheumatic valvular heart disease or infective endocarditis, cardiac
valves express angiogenic factors leading to neovascularization. Thickening of the
adult cardiac valves, which leads to congestive heart failure, such as in aortic
stenosis, occurs by dysregulation of angiogenesis inhibitors, such as endostatin and
chondromodulin-1 [ 499 ]. Anti-angiogenesis therapy is used against cancer.

10.7.2.1 Peptidic Inhibitors of Endothelial Cell Proliferation

and Migration

A large number of peptides inhibit proliferation and migration of endothelial
cells. They include substances derived from members of families of collagen-4,
thrombospondins, 81 thrombospondin motif-containing proteins, such as ADAM9
and ADAM12, ADAMTS1 to ADAMTS20, semaphorin-5A and -5B, and Wnt1-
inducible signaling pathway protein WISP1 to WISP3, CXC chemokines, so-
matotropins, serpins, kringle-containing proteins, such as thrombin, coagulation
factor-XII, tissue thromboplastin activator, and kremen-1 and -2, and peptides
derived from pro-angiogenic proteins [ 1341 ].
Whereas vascular endothelial growth factor receptor-2 in endothelial cells
activates phospholipase-C 1 during angiogenesis, casitas-B-lineage lymphoma

ubiquitin ligase (CBL) forms a complex with PLC

γ

γ 1 and VEGFR2 and precludes

angiogenesis [ 1342 ].

80 Soluble VEGFR1 S also binds VEGFb and placenta growth factor. Agent VEGFR1 S forms
heterodimers with VEGFR2 receptor. Avascularity may be maintained by multiple redundant
mechanisms associated with many anti-angiogenic molecules that exist in the cornea, but neutral-
ization of VEGFR1 S alone abolishes corneal avascularity. VEGFR1 S also regulates the availability
of VEGFa in cyclic vascularization and embryonic sprouting.
81 Thrombospondins constitute 2 subsets: subset A with Tsp1 and Tsp2 homotrimers and subset B
with Tsp3 to Tsp5 homopentamers.