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(Hypertension. 2003;41:156.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Enhancement of Ischemia-Induced Angiogenesis by eNOS Overexpression

Katsuya Amano; Hiroaki Matsubara; Osamu Iba; Mitsuhiko Okigaki; Soichiro Fujiyama; Takanobu Imada; Hiroyuki Kojima; Yoshihisa Nozawa; Seinosuke Kawashima; Mitsuhiro Yokoyama; Toshiji Iwasaka

From the Department of Medicine II and Cardiovascular Center (K.A., H.M., O.I., M.O., S.F., T. Imada, T. Iwasaka) and Radiology (H.K.), Kansai Medical University, Moriguchi, Osaka, Japan; Pharmacobioregulation Research Laboratory, Taiho Pharmaceutical Co Ltd (Y.N.), Saitama, Japan; and the Division of Cardiovascular and Respiratory Medicine, Kobe University Graduate School of Medicine (S.K., M.Y.), Kobe, Japan.

Correspondence to Hiroaki Matsubara, MD, Department of Medicine II, Kansai Medical University, Moriguchi, Osaka 570-8507, Japan. E-mail matsubah{at}takii.kmu.ac.jp

It remains undetermined whether continuous endothelial nitric oxide (NO) overexpression exerts angiogenic action. We surgically induced hindlimb ischemia in transgenic mice overexpressing endothelial NO synthase in the endothelium (eNOS-Tg) and studied neocapillary formation, ischemia-induced vascular endothelial growth factor (VEGF) expression, cGMP accumulation, and Akt/PKB signaling. Laser Doppler imaging revealed a markedly increased recovery of blood perfusion in ischemic limbs of eNOS-Tg mice (44% increase) compared with that in wild-type mice. Angiography showed a marked increase in basal and ischemia-induced collateral vessel formation in eNOS-Tg mice. Basal capillary densities and tissue cGMP levels were increased in eNOS-Tg mice (1.8-fold and 1.6-fold versus wild-type mice, respectively). Ischemia-induced neocapillary formation and cGMP accumulation were markedly increased in eNOS-Tg mice (3.6-fold and 4.1-fold versus preischemia levels, respectively), whereas those in wild-type mice were much less (1.8-fold and 1.5-fold, respectively). Basal and time-dependent VEGF expression in ischemic muscles did not differ between eNOS-Tg and wild-type mice. Basal and VEGF-mediated Akt phosphorylation in aortas was similar between eNOS-Tg and wild-type mice. Aortic basal eNOS expression was increased 3.3-fold, and VEGF-mediated eNOS phosphorylation was markedly induced in aortas of eNOS-Tg compared with preischemia levels (4.2-fold), whereas much smaller changes were observed in wild-type mice (1.8-fold increase). Our study demonstrates that overexpression of eNOS protein causes a marked increase in neocapillary formation in response to tissue ischemia without affecting ischemia-induced VEGF expression or VEGF-mediated Akt phosphorylation.

Key Words: endothelium • ischemia • nitric oxide synthase • nitric oxide • vasculature

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