Objective-In response to changes in wall shear stress (WSS) the vascular endothelium releases several factors, among others nitric oxide. On the basis of studies of endothelial cells in culture, suggesting that platelet endothelial cell adhesion molecule-1 (PECAM-1) is specifically involved in sensing and coupling high temporal gradients of fluid shear stress with activation of eNOS, we hypothesized that dilations of isolated skeletal muscle arterioles from PECAM-1 knockout mice (PECAM-KO) will be reduced to rapid increases in WSS elicited by increases in perfusate flow. Methods and Results-Small and large step increases in flow resulted in substantial dilations in arterioles of WT mice (45Ϯ4%), but they were markedly reduced in arterioles of PECAM-KO mice (22Ϯ5%). The initial slope of dilations, when WSS increased rapidly, was greater in vessels of WT than those of PECAM-KO mice (slopes: 0.378 and 0.094, respectively), whereas the second phase of dilations, when flow/shear stress was steady, was similar in the 2 groups (slopes: 0.085 and 0.094, respectively). Inhibition of eNOS significantly reduced the initial phase of dilations in arterioles from WT, but not from those of PECAM-KO mice. The calcium ionophore A23187 elicited similar NO-mediated dilation in both WT and PECAM-KO mice. Conclusions-In isolated arterioles of PECAM-KO mice activation of eNOS and consequent dilation by agonists is maintained, but the dilation to high temporal gradients of wall shear stress elicited by increases in perfusate flow is reduced. Thus, we propose that PECAM-1 plays an important role in the ability of the endothelium to sense and couple high temporal gradients of wall shear stress to NO-mediated arteriolar dilation during sudden changes in blood flow in vivo. Key Words: PECAM-1 Ⅲ arteriole Ⅲ endothelium Ⅲ flow-induced dilation Ⅲ nitric oxide T he vascular endothelium is uniquely situated to act as the signal transduction interface between hemodynamic forces and the underlying vascular smooth muscle. Increases in shear stress have long been shown to result in vasodilatation mediated, in part, by the endothelium-dependent release of nitric oxide (NO). 1-5 Since endothelium-derived NO was first identified and characterized, fluid shear stress has been established as the most potent stimulus that regulates the activity of endothelial NO synthase (eNOS). 6 We have shown previously that stepwise increases in perfusate flow, via increases in wall shear stress, elicit substantial dilations of isolated arterioles. [3][4][5] Recent in vitro studies in cultured endothelial cells showed that the sudden onset of fluid flow induces a burst of NO production, which seemed to be related more to the magnitude of temporal gradient of shear stress than to its absolute value, 6,7 suggesting that the vascular endothelium is able to discriminate between temporal gradients of shear stress as also proposed by others.7a The molecular basis of shear stress-induced mechanochemical signal transduction, and the endothelium's ability to discriminate betw...
Background Annexin A1 is expressed specifically on the tumour vasculature surface. Intravenously injected IF7 targets tumour vasculature via annexin A1. We tested the hypothesis that IF7 overcomes the blood–brain barrier and that the intravenously injected IF7C(RR)-SN38 eradicates brain tumours in the mouse. Methods (1) A dual-tumour model was generated by inoculating luciferase-expressing melanoma B16 cell line, B16-Luc, into the brain and under the skin of syngeneic C57BL/6 mice. IF7C(RR)-SN38 was injected intravenously daily at 7.0 μmoles/kg and growth of tumours was assessed by chemiluminescence using an IVIS imager. A similar dual-tumour model was generated with the C6-Luc line in immunocompromised SCID mice. (2) IF7C(RR)-SN38 formulated with 10% Solutol HS15 was injected intravenously daily at 2.5 μmoles/kg into two brain tumour mouse models: B16-Luc cells in C57BL/6 mice, and C6-Luc cells in nude mice. Results (1) Daily IF7C(RR)-SN38 injection suppressed tumour growth regardless of cell lines or mouse strains. (2) Daily injection of Solutol-formulated IF7C(RR)-SN38 led into complete disappearance of B16-Luc brain tumour in C57BL/6 mice, whereas this did not occur in C6-Luc in nude mice. Conclusions IF7C(RR)-SN38 crosses the blood–brain barrier and suppresses growth of brain tumours in mouse models. Solutol HS15-formulated IF7C(RR)-SN38 may have promoted an antitumour immune response.
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