Negative regulation of VEGF-induced vascular leakage by blockade of angiotensin II type 1 receptor.
OBJECTIVE
Permeability of blood vessels is essential for tissue homeostasis. However, disorganized hyperpermeability leads to progression of diseases. Vascular endothelial growth factor-A (VEGF) is a key regulator for leakiness of blood vessels and it has been reported that VEGF-mediated hyperpermeability was suppressed by angiopoietin-1 (Ang1). We found that Angiotensin-converting enzyme (ACE) was downregulated in endothelial cells by Ang1. ACE converts angiotensin I to angiotensin II (AII). Here, we studied the relationship between VEGF and AII relative to vascular permeability.


RESULTS
We showed that VEGF-mediated vascular hyperpermeability was suppressed in mice given AII type 1 receptor (AT1R) blocker (ARB); the effect was also seen in AT1R-deficient mice. In this system, we found that ARB inhibited VEGF-induced gap formation. Furthermore, we ascertained that angioedema induced by overexpression of VEGF decreased noticeably in ARB-treated ischemic mice.


CONCLUSIONS
Because ARB suppressed VEGF-induced vascular hyperpermeability, we propose that ARB may be used to minimize the risk of edema in therapeutic angiogenesis using VEGF.
Sano
Hideto
H
Department of Stem Cell Biology, Cancer Research Institute, Kanazawa University, 13-1, Takara-machi, Kanazawa, Ishikawa, 920-0934 Japan.
Hosokawa
Kohei
K
Kidoya
Hiroyasu
H
Takakura
Nobuyuki
N
D000799:Angioedema / Q000503:physiopathology; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D000804:Angiotensin II / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002199:Capillary Permeability / Q000502:physiology; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein; D000099152:Cadherin 5
D042683:Angiopoietin-1; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers; D015703:Antigens, CD; D015820:Cadherins; D008565:Membrane Proteins; D007703:Peptidyl-Dipeptidase A; D010750:Phosphoproteins; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D042461:Vascular Endothelial Growth Factor A; D062826:Zonula Occludens-1 Protein; D000099152:Cadherin 5; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; C467484:VEGFA protein, human; C467480:vascular endothelial growth factor A, mouse