Investigation of Vascular Responses in Endothelial Nitric Oxide Synthase/Cyclooxygenase-1 Double-Knockout Mice

Abstract

Background-Endothelium-dependent dilatation is mediated by 3 principal vasodilators: nitric oxide (NO), prostacyclin (PGI 2 ), and endothelium-derived hyperpolarizing factor (EDHF). To determine the relative contribution of these factors in endothelium-dependent relaxation, we have generated mice in which the enzymes required for endothelial NO and PGI 2 production, endothelial NO synthase (eNOS) and cyclooxygenase-1 (COX-1), respectively, have been disrupted (eNOS Ϫ/Ϫ and COX-1 Ϫ/Ϫ mice). Methods and Results-In female mice, the absence of eNOS and COX-1 had no effect on mean arterial blood pressure (BP), whereas BP was significantly elevated in eNOS Ϫ/Ϫ /COX-1 Ϫ/Ϫ males compared with wild-type controls. Additionally, endothelium-dependent relaxation remained intact in the resistance vessels of female mice and was associated with vascular smooth muscle hyperpolarization; however, these responses were profoundly suppressed in arteries of male eNOS Ϫ/Ϫ /COX-1 Ϫ/Ϫ animals. Similarly, the endothelium-dependent vasodilator bradykinin produced dose-dependent hypotension in female eNOS Ϫ/Ϫ /COX-1 Ϫ/Ϫ animals in vivo but had no effect on BP in male mice. Conclusions-These studies indicate that EDHF is the predominant endothelium-derived relaxing factor in female mice, whereas NO and PGI 2 are the predominant mediators in male mice. Moreover, the gender-specific prevalence of EDHF appears to underlie the protection of female eNOS

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study

“…Hypertension, a known complication of VEGFR signalling inhibition, is likely related with several factors, including diminished nitric oxide and prostacyclin synthesis (Scotland et al, 2005), diminished endothelial baroreceptor response (Yang et al, 2002), small artery and arteriole rarefaction (Ciuffetti et al, 2003) as well as increased vascular stiffness (Veronese et al, 2006). To our knowledge, this is the first clinical trial among malignant glioma patients to note an association between hypertension after VEGF-targeted therapy and improved outcome.…”

Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

“…In small arteries, endothelium‐dependent relaxation in males was found to rely more heavily on NOS than EDH, and the opposite was found for females 14, 15, 38, 39. No role for COX‐derived prostanoids was found in either sex 12, 14, 15.…”

Sex differences in vascular function: implication of endothelium-derived hyperpolarizing factor

“…crucial in this modulation, especially given the fact that in the resistance vasculature the predominant mediators implicated in endothelium-dependent relaxation in males are NO and PGI 2 , whereas in females it is EDHF (McCulloch & Randall 1998, Pak et al 2002, Scotland et al 2005b.…”

“…Moreover, the administration of the endothelium-dependent dilator bradykinin, to female dKOs, causes a dose-dependent decrease in arterial blood pressure, while this vasoactive peptide has no effect in the male dKO animals; this result was mirrored in mesenteric arteries in vitro, where endotheliumderived relaxation stimulated by acetylcholine was significantly greater in females. Since EDHF plays a more prominent role in endothelium-dependent relaxation of resistance versus conduit arteries (Shimokawa et al 1996), data from the EDHF mouse suggests that sex hormones regulate EDHF activity and that this may play a critical role in the maintenance of physiological levels of blood pressure and endothelial function in females (Scotland et al 2005b). Consequently, enhanced EDHF function in females compared with males (McCulloch & Randall 1998, Pak et al 2002, Scotland et al 2005b) might afford the cardioprotective phenotype of females.…”