The myogenic response (MR) may represent an important physiological parameter underlying arterial blood pressure (BP). We studied the effects of age, gender, and BP on the MR of mesenteric arteries from 8- to 52-wk-old mice. Increasing age and BP are associated with an increase in the perfusion pressure at which tone develops (myogenic set point). An inverse correlation exists between age and extent (magnitude) of the MR in male (r(2) = 0.93, P = 0.0087) and female mice (r(2) = 0.90, P = 0.013) as well as between BP and extent of the MR in male (r(2) = 0.96, P = 0.0036) and female (r(2) = 0.90, P = 0.014) mice. In contrast, the strength of the MR (slope of active diameter-pressure relationship) and phenylephrine-mediated constriction did not differ among these groups. Although gender had no effect on MR at any perfusion pressure or age, only male mice showed significant salt-induced hypertension and an associated increase in the set point and reduction in the extent of the MR. The set point and extent of the MR is linked to the in vivo pressure during development and experimental hypertension.

Abstract-In vascular smooth muscle cells (SMCs), several mechanisms act in concert to regulate the intracellular calcium concentration [Ca 2ϩ ] i , which may in turn affect vascular tone. One such mechanism is the extrusion of Ca 2ϩ by the plasma membrane calcium ATPase (PMCA). To address, in particular, the role of the neuronal nitric oxide synthase (nNOS)-associating isoform PMCA4b in regulating vascular tone, a doxycycline-responsive transgene for human PMCA4b was overexpressed in arterial SMCs of mice. Overexpression of hPMCA4b resulted in a 2-fold increase in total aortic PMCA4 protein expression and significant real-time RT-PCR-documented differences in the levels of endogenous mouse PMCA1, PMCA4, SERCA2, and IP3R1 gene expression in arterial SMCs. Whereas no significant difference in basal [Ca 2ϩ ] i or Ca 2ϩ sensitivity was observed in vascular SMCs or mesenteric arteries, respectively, from hPMCA4b-overexpressing versus control mice, hPMCA4b-overexpressing mice revealed a reduced set-point and increased extent of myogenic response and heightened sensitivity to vasoconstrictors. Treatment of arteries with an nNOS inhibitor resulted in a reduced set-point and increased extent of the myogenic response in control but not hPMCA4b-overexpressing mice. Moreover, aortic SMCs from hPMCA4b-overexpressing mice exhibited reduced levels of cGMP under both basal and phenylephrine-stimulated conditions. These changes were associated with significant doxycycline-reversible elevations in blood pressure. Taken together, these data show that overexpression of hPMCA4b in arterial SMCs increases vascular reactivity and blood pressure, an effect that may be mediated in part by negative regulation of nNOS. Key Words: transgenic mice Ⅲ blood pressure Ⅲ nitric oxide synthase Ⅲ intracellular calcium Ⅲ myogenic tone H ypertension is a polygenic disease responsive to environmental factors. Although more than 50 genes have been implicated in the regulation of blood pressure, 1 the complexity of hypertension has been additionally revealed by studies suggesting that insertion or deletion of single genes can lead to either reduced or elevated blood pressure. 2 One hallmark of hypertension is increased peripheral resistance attributable to both structural and functional changes in resistance arteries. 3 On a functional level, peripheral resistance is a balance between vasodilator and vasoconstrictor mechanisms of vascular smooth muscle cells (SMCs), in turn dependent on the intracellular calcium concentration ([Ca 2ϩ ] i ) and the Ca 2ϩ sensitivity of the contractile apparatus. Homeostasis of Ca 2ϩ involves several distinct mechanisms, including the extrusion of Ca 2ϩ by plasma membrane calcium ATPase (PMCA). These high-affinity calmodulin-responsive Ca 2ϩ efflux pumps are P-type transport proteins encoded for by a family of 4 genes (PMCA1 through PMCA4). Both PMCA1 and PMCA4 are ubiquitously expressed, whereas PMCA2 and PMCA3 show cell-specific patterns of expression. 4 From these 4 genes, more than 20 distinct isoforms of PMCA ...