Published online before print January 16, 2003, doi: 10.1161/01.RES.0000056757.93432.8C
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Submitted on October 17, 2002
Revised on December 20, 2002
Accepted on January 7, 2003
Nitric Oxide Enhances Angiogenesis via the Synthesis of Vascular Endothelial Growth Factor and cGMP After Stroke in the Rat
Ruilan Zhang ;
From the Department of Neurology (R.Z., L.W., L.Z., J.C., Z. Zhang, M.C.), Henry Ford Health Sciences Center, Detroit, Mich; the Department of Antibody Technology (Z. Zhu), ImClone Systems Incorporated, New York, NY; and the Department of Physics (M.C.), Oakland University, Rochester, Mich.
* To whom correspondence should be addressed. E-mail: chopp{at}neuro.hfh.edu.
We investigated the effects of NO on angiogenesis and the synthesis of vascular endothelial growth factor (VEGF) in a model of focal embolic cerebral ischemia in the rat. Compared with control rats, systemic administration of an NO donor, DETANONOate, to rats 24 hours after stroke significantly enlarged vascular perimeters and increased the number of proliferated cerebral endothelial cells and the numbers of newly generated vessels in the ischemic boundary regions, as evaluated by 3-dimensional laser scanning confocal microscopy. Treatment with DETANONOate significantly increased VEGF levels in the ischemic boundary regions as measured by ELISA. A capillary-like tube formation assay was used to investigate whether DETANONOate increases angiogenesis in ischemic brain via activation of soluble guanylate cyclase. DETANONOate-induced capillary-like tube formation was completely inhibited by a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ). Blocking VEGF activity by a neutralized antibody against VEGF receptor 2 significantly attenuated DETANONOate-induced capillary-like tube formation. Moreover, systemic administration of a phosphodiesterase type 5 inhibitor (Sildenafil) to rats 24 hours after stroke significantly increased angiogenesis in the ischemic boundary regions. Sildenafil and an analog of cyclic guanosine monophosphate (cGMP) also induced capillary-like tube formation. These findings suggest that exogenous NO enhances angiogenesis in ischemic brain, which is mediated by the NO/cGMP pathway. Furthermore, our data suggest that NO, in part via VEGF, may enhance angiogenesis in ischemic brain.
Key words: nitric oxide • phosphodiesterase type 5 inhibitor • vascular endothelial growth factor • angiogenesis • cerebral ischemia
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