Enhanced Release of Prostaglandins Contributes to Flow-Induced Arteriolar Dilation in eNOS Knockout Mice

Abstract

Abstract-Nitric oxide and prostaglandins were shown to contribute to the endothelial mediation of flow-induced dilation of skeletal muscle arterioles of rats. Thus, we hypothesized that flow-induced dilation and its mediation are altered in gracilis muscle arterioles of mice deficient in the gene for endothelial nitric oxide synthase (eNOS-KO) compared with control wild-type (WT) mice. Gracilis muscle arterioles (Ϸ80 m) of male mice were isolated, then cannulated and pressurized in a vessel chamber. The increases in diameter elicited by increases in perfusate flow from 0 to 10 L/min were similar in arterioles from eNOS-KO (nϭ28) and WT (nϭ22) mice (Ϸ20 m at 10 L/min flow). Removal of the endothelium eliminated flow-induced dilations in vessels of both strains of mice.Ϫ4 mol/L) significantly inhibited flow-induced dilation in arterioles of WT mice by Ϸ51% but had no effect on responses of arterioles from eNOS-KO mice. Indomethacin (INDO, 10 Ϫ5 mol/L) inhibited flow-induced dilation of WT mice by Ϸ49%, whereas it completely abolished this response in arterioles of eNOS-KO mice. Simultaneous administration of INDO and L-NNA eliminated flow-induced responses in arterioles of WT mice. Dilations to carbaprostacyclin were similar at concentrations of 10 Ϫ8 and 3ϫ10 Ϫ8 mol/L but decreased significantly at 10 Ϫ7 mol/L in arterioles of eNOS-KO compared with those of WT mice. These findings demonstrate that, despite the lack of nitric oxide mediation, flow-induced dilation is close to normal in arterioles of eNOS-KO mice because of an enhanced release of endothelial dilator prostaglandins and suggest that this vascular adaptation may contribute to the regulation of peripheral resistance in eNOS-KO mice. (Circ Res. 1999;85:288-293.) Key Words: transgenic mice Ⅲ intraluminal flow Ⅲ endothelium Ⅲ nitric oxide Ⅲ prostacyclin C onsiderable evidence demonstrates that endotheliumderived nitric oxide (NO) plays a critical role in the regulation of vascular tone. 1-3 One of the important mechanisms through which NO release is controlled is by alterations in wall shear stress during changes in blood flow. 3,4 Previous studies demonstrated that increases in perfusate flow elicit endotheliumdependent dilation of gracilis muscle arterioles, a response that is mediated by the combined release of NO and prostaglandins. 5 It has also been demonstrated that reduced release of NO could lead to an enhanced arteriolar resistance, which may be involved in the pathogenesis of cardiovascular disorders, such as hypertension and atherosclerosis. 6,7 The importance of the NO-related dilator mechanism is further underlined by studies showing a significant increase in blood pressure during systemic inhibition of nitric oxide synthase (NOS) with L-arginine analogs 8,9 or when the gene encoding endothelial nitric oxide synthase (eNOS) is disrupted. 10,11 Interestingly, however, there are quantitative differences in blood pressure in response to systemic administration of L-arginine analogs in wild-type (WT) mice compared with the level of blood pressur...

Evidence for a Functional Role of Endothelial Transient Receptor Potential V4 in Shear Stress–Induced Vasodilatation

“…Release of AA and production of AA metabolites in response to flow is well documented in cultured ECs, 32 and a role of AA metabolites in flow-induced vasodilatation has been proposed previously. 31 With respect to TRPV4, exogenously applied AA has been shown to activate rat TRPV4 as shown here and cloned TRPV4 previously, 5 and endogenously produced AA mediates mechanical activation of TRPV4 by cell swelling. 24 These roles of AA in both shear stressinduced vasodilatation and TRPV4 activation tempted us to speculate that PLA 2 -mediated AA release after shear stress stimulation mediates TRPV4 activation.…”

“…In the present study, we found that an increase in shear stress caused vasodilatation of rat CAs and of small-sized A gracilis in a strictly NO-dependent fashion, which is in agreement with findings in arteries of humans 29 and other species; 30 whereas in mice, both prostaglandins as well as NO mediate this type of vasodilatation. 31 Similar to 4␣PDD-induced vasodilatation, shear stress-induced vasodilatation in rat CAs was greatly blocked by the TRPV4 inhibitor RuR as well as by buffering endothelial [Ca 2ϩ ] i with BAPTA-AM, suggesting an involvement of TRPV4 in this response. Inhibition of PKC and of TK was without effect, suggesting that protein phosphorylation or potential TRPV4 phosphorylation by one of these kinases does not seem to play a major role in shear stress-induced vasodilatation or activation.…”

Chronic diet-induced hyperhomocysteinemia impairs eNOS regulation in mouse mesenteric arteries

“…Studies in which nitric oxide has been blocked pharmacologically or by genetic knockout of eNOS have shown a general compensation for the loss of nitric oxide by upregulation of EDHF or prostacyclin (4,6,16,27). General compensation by combined non-nitric oxide mechanisms is not indicated in the present study, because there is no difference in dilation between control and HHcy arteries with L-NAME (Fig.…”

Novel Mechanism of Vasodilation in Inflammatory Bowel Disease

“…31 Sun et al showed that flow-induced dilation is mediated by both endothelial NO and prostaglandins in skeletal muscle arterioles from wild-type mice, but is mediated exclusively by prostaglandins in male endothelial NO synthase knockout mice. 32 In each case the compensatory PG dilator was derived from the endothelium. 31,32 These data suggest that certain vessels have the ability to compensate for the loss of one endothelium-dependent vasodilator mechanism by upregulating an alternative endothelium-dependent dilator system (EDHF or prostaglandins).…”

“…32 In each case the compensatory PG dilator was derived from the endothelium. 31,32 These data suggest that certain vessels have the ability to compensate for the loss of one endothelium-dependent vasodilator mechanism by upregulating an alternative endothelium-dependent dilator system (EDHF or prostaglandins).…”