Evidence for the importance of angiotensin II type 1 receptor in ischemia-induced angiogenesis.
The role of the renin-angiotensin system (RAS) in angiogenesis is little known. Here, we show that the angiotensin II (ATII) type 1 (AT1) receptor plays an important role in ischemia-induced angiogenesis. Well-developed collateral vessels and angiogenesis were observed in wild-type (WT) mice in response to hindlimb ischemia, whereas these responses were reduced in ATII type 1a receptor knockout (AT1a(-/-)) mice. Ischemia-induced angiogenesis was also impaired in WT mice treated with the AT1 receptor blocker TCV-116. These effects were not due to reduced systemic blood pressure (SBP), because hydralazine treatment preserved angiogenesis in WT mice although it reduced SBP to a level similar to that of AT1a(-/-) mice. Infiltration of inflammatory mononuclear cells (MNCs), including macrophages and T lymphocytes, was suppressed in the ischemic tissues of AT1a(-/-) mice compared with WT mice. Double immunofluorescence staining revealed that infiltrated macrophages and T lymphocytes expressed VEGF, and the expression of VEGF and monocyte chemoattractant protein-1 was also decreased in AT1a(-/-). Finally, the impaired angiogenesis in AT1a(-/-) mice was rescued by intramuscular transplantation of MNCs obtained from WT mice, further indicating the importance of MNC infiltration in ischemia-induced angiogenesis. Thus, the ATII--AT1 receptor pathway promotes early angiogenesis by supporting inflammatory cell infiltration and angiogenic cytokine expression.
Sasaki
Ken
K
The Cardiovascular Research Institute, and Department of Internal Medicine III, Kurume University School of Medicine, Kurume, Japan.
Murohara
Toyoaki
T
Ikeda
Hisao
H
Sugaya
Takeshi
T
Shimada
Toshifumi
T
Shintani
Satoshi
S
Imaizumi
Tsutomu
T
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002196:Capillaries / Q000473:pathology; D018932:Chemokine CCL2 / Q000502:physiology; D016228:Endothelial Growth Factors / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply; D006830:Hydralazine / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D007511:Ischemia / Q000150:complications* / Q000503:physiopathology*; D007963:Leukocytes, Mononuclear / Q000473:pathology / Q000637:transplantation; D008222:Lymphokines / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000503:physiopathology*; D011725:Pyridines / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D057911:Angiotensin Receptor Antagonists; D018932:Chemokine CCL2; D016228:Endothelial Growth Factors; D007093:Imidazoles; D008222:Lymphokines; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C073402:PD 123319; D006830:Hydralazine