VEGF modulates NO production: the basis of a cytoprotective effect?

Abstract

Though it is well established that vascular endothelial VEGF signaling may activate Hsp90 or an Hsp90 associgrowth factor (VEGF) plays a key role in the development ated protein, thereby increasing its affinity for eNOS, and of blood vessels in embryogenesis and in disease, two that this association stimulates NOS activation [7]. It is questions which have remained enigmatic have been the suggested that Hsp90 may act as an allosteric modulator of mechanism through which VEGF acts and the functions of eNOS by inducing a conformational change or by stabilizVEGF in normal adult blood vessels. An important deing the dimeric form. velopment towards the answer to these questions has been An important question raised by all these studies is the the discovery from our own and other laboratories that function of VEGF regulated NO production. NO has been VEGF can stimulate the production of nitric oxide and implicated in angiogenesis and compelling evidence for prostacyclin in endothelial cells [1–4]. These two factors this has come from the work of Murohara et al. who are vasodilators and stimulate several other functions demonstrated that eNOS is critical for angiogenesis in which may be protective of blood vessels such as the tissue ischaemia of which a major stimulator is VEGF [8]. inhibition of both smooth muscle cell (SMC) proliferation We recently proposed another important role for VEGFand platelet aggregation. regulated NO production in the protection of blood vessels A new twist to this story comes from the report in this against intimal VSMC hyperplasia. This hypothesis is issue by Bouloumie et al. [5] that VEGF increases based on the observations that VEGF gene transfer in endothelial nitric oxide synthase (eNOS) expression in rabbit carotid arteries reduces intimal thickening [2] and cultured endothelial cells. VEGF also led to an up-regulathat VEGF releases NO, and prostacyclin (PGI ) from 2 tion of eNOS mRNA and protein expression in ‘native‘ endothelial cells [2,3]. Such a response might be important endothelial cells from rat aortae. Their results indicate that in protecting the adult artery from injury and other in addition to the short-term stimulation of eNOS activity proliferative stimuli. Inflammatory cytokines (IL-1b), 21 already described following an acute increase in [Ca ] growth factors (bFGF and PDGF) and hypoxia – all [1], VEGF exerts a long-term stimulatory effect on endofeatures of the atherosclerotic microenviroment – all cause thelial NO generation by increasing eNOS expression. This the secretion of VEGF from SMC and cooperate with each conclusion is supported by a VEGF-induced increase in other to further enhance VEGF expression [9]. Since NO basal cGMP levels in cultured endothelial cells and a and PGI inhibit smooth muscle cell replication, by 2 leftward shift of the concentration-response curve to increasing cGMP and cAMP respectively, then VEGFacetylcholine in rat aortic rings. stimulated production of NO and PGI from the endo2 These findings are consistent with the results of Papapetthelium might inhibit inappropriate SMC proliferation in ropoulos A. et al. which show that VEGF stimulates an atherosclerosis and in other lesions which might arise from increase in eNOS protein and the release of nitric oxide in inappropriate stimulation by inflammatory cytokines, human umbilical vein endothelial cells (HUVEC) after 24 growth factors or hypoxia. hours [6]. In addition, Bouloumie et al. show that the This cytoprotective role, since it does not involve stimulatory effect of VEGF on eNOS mRNA upregulation angiogenesis or endothelial cell repair [2], may represent a is due to an enhancement of its stability. Another insight new paradigm for the action of VEGF in the adult into how VEGF may enhance eNOS activity has come vasculature [Fig. 1]. The ability of VEGF to cause from Guillermo Garcia-Cardena et al. who reported that sustained release of NO through enhanced expression of eNOS as described in this paper, might be a further