Angiogenesis-Dependent and Independent Phases of Intimal Hyperplasia

Abstract

Background-Neointimal vascular smooth muscle cell (VSMC) proliferation is a primary cause of occlusive vascular disease, including atherosclerosis, restenosis after percutaneous interventions, and bypass graft stenosis. Angiogenesis is implicated in the progression of early atheromatous lesions in animal models, but its role in neointimal VSMC proliferation is undefined. Because percutaneous coronary interventions result in induction of periadventitial angiogenesis, we analyzed the role of this process in neointima formation. Methods and Results-Local injury to the arterial wall in 2 different animal models induced periadventitial angiogenesis and neointima formation. Application of angiogenesis stimulators vascular endothelial growth factor (VEGF-A 165 ) or a proline/arginine-rich peptide (PR39) to the adventitia of the injured artery induced a marked increase in neointimal thickening beyond that seen with injury alone in both in vivo models. Inhibition of either VEGF (with soluble VEGF receptor 1 [sFlt1]) or fibroblast growth factor (FGF) (with a dominantϭnegative form of FGF receptor 1 [FGF-R1DN]), respectively, signaling reduced adventitial thickening induced by VEGF and PR39 to the level seen with mechanical arterial injury alone. However, neither inhibitor was effective in preventing neointimal thickening after mechanical injury when administered in the absence of angiogenic growth factor. Conclusions-Our findings indicate that adventitial angiogenesis stimulates intimal thickening but does not initiate it.

Local delivery of VEGF adenovirus to the uterine artery increases vasorelaxation and uterine blood flow in the pregnant sheep

“…Adenoviral constructs (E1,E3-deleted) encoding either VEGF-A 165 (Ad.VEGF-A), VEGF-D (Ad.VEGF-D) or LacZ (Ad.LacZ) were produced by Ark Therapeutics, Finland, as described. 21 We studied Romney breed time-mated ewes that were pregnant with singleton (n ¼ 3) or twin (n ¼ 3) fetuses between 88 and 102 days of gestation (term 145 days of gestation); the gestational age was confirmed using ultrasound examination of fetal size.…”

Critical role of the NADPH oxidase subunit p47phox on vascular TLR expression and neointimal lesion formation in high-fat diet-induced obesity

“…14,19 Angiogenesis has likewise been implicated in neointimal formation. 41 Animal models also reveal that angiogenesis is increased after the first 4 weeks of an HF diet. 42 Treatment with the angiogenesis inhibitors prevents lesion progression in ApoE À/À mice.…”

Angiogenesis in Atherogenesis

“…17 Whether this concept can be extended to non-mechanical arterial injury awaits confirmation. Furthermore, it would be intriguing to answer the question whether stimulation of angiogenesis without manipulation of any component of the vascular wall initiates an atherosclerotic lesion.…”