Angiogenesis-dependent and independent phases of intimal hyperplasia.
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.


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-A165) 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 dominant=negative 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.
Khurana
Rohit
R
Centre for Cardiovascular Biology and Medicine, Department of Medicine, University College, London, UK.
Zhuang
Zhenwu
Z
Bhardwaj
Shalini
S
Murakami
Masahiro
M
De Muinck
Ebo
E
Yla-Herttuala
Seppo
S
Ferrara
Napoleone
N
Martin
John F
JF
Zachary
Ian
I
Simons
Michael
M
D043925:Angiogenesis Inducing Agents; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D020212:Carotid Artery Injuries / Q000503:physiopathology; D002404:Catheterization / Q000009:adverse effects; D016220:Fibroblast Growth Factor 1 / Q000037:antagonists & inhibitors / Q000502:physiology; D006965:Hyperplasia; D008297:Male; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D018919:Neovascularization, Physiologic; D011506:Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012995:Solubility; D017539:Tunica Intima / Q000473:pathology*; D014651:Vasa Vasorum / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D043925:Angiogenesis Inducing Agents; D023181:Antimicrobial Cationic Peptides; C501730:PR 11 proline-arginine-rich peptide; D011506:Proteins; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016220:Fibroblast Growth Factor 1; C072212:PR 39; C496350:Fgfr1 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1