Differential [Ca ]i signaling of vasoconstriction in mesenteric microvessels of normal and reduced uterine perfusion pregnant rats

Chen W, Khalil RA. Differential [Ca ]i signaling of vasoconstriction in mesenteric microvessels of normal and reduced uterine perfusion pregnant rats. Am J Physiol Regul Integr Comp Physiol 295: R1962–R1972, 2008. First published October 8, 2008; doi:10.1152/ajpregu.90523.2008.—Vascular resistance and blood pressure (BP) are reduced during late normal pregnancy (Norm-Preg). In contrast, studies in human preeclampsia and in animal models of hypertension in pregnancy (HTN-Preg) have suggested that localized reduction in uterine perfusion pressure (RUPP) in late pregnancy is associated with increased systemic vascular resistance and BP; however, the vascular mechanisms involved are unclear. Because Ca is a major determinant of vascular contraction, we hypothesized that the intracellular free calcium concentration ([Ca ]i) signaling of vasoconstriction is differentially regulated in systemic microvessels during normal and RUPP in late pregnancy. Pressurized mesenteric microvessels from Norm-Preg and RUPP rats were loaded with fura 2 in preparation for simultaneous measurement of diameter and [Ca ]i (presented as fura 2 340/380 ratio). Basal [Ca ]i was lower in RUPP (0.73 0.03) compared with Norm-Preg rats (0.82 0.03). Membrane depolarization by 96 mM KCl, phenylephrine (Phe, 10 5 M), angiotensin II (ANG II, 10 7 M), or endothelin-1 (ET-1, 10 7 M) caused an initial peak followed by maintained vasoconstriction and [Ca ]i. KCl caused similar peak vasoconstriction and [Ca ]i in Norm-Preg (45.5 3.3 and 0.89 0.02%) and RUPP rats (46.3 2.1 and 0.87 0.01%). Maximum vasoconstriction to Phe, ANG II, and ET-1 was not significantly different between Norm-Preg (28.6 4.8, 32.5 6.3, and 40 4.6%, respectively) and RUPP rats (27.8 5.9, 34.4 4.3, and 38.8 4.1%, respectively). In contrast, the initial Phe-, ANG II-, and ET-1-induced 340/380 ratio ([Ca ]i) was reduced in RUPP (0.83 0.02, 0.82 0.02, and 0.83 0.03, respectively) compared with Norm-Preg rats (0.95 0.04, 0.93 0.01, and 0.92 0.02, respectively). Also, the [Ca ]i-vasoconstriction relationship was similar in KCl-treated but shifted to the left in Phe-, ANG II-, and ET-1-treated microvessels of RUPP compared with Norm-Preg rats. The lower agonist-induced [Ca ]i signal of vasoconstriction and the leftward shift in the [Ca ]i-vasoconstriction relationship in microvessels of RUPP compared with Norm-Preg rats suggest activation of [Ca ]i sensitization pathway(s). The similarity in vasoconstriction in RUPP and Norm-Preg rats suggests that such a [Ca ]i sensitization pathway(s) may also provide a feedback effect on Ca mobilization/homeostatic mechanisms to protect against excessive vasoconstriction in systemic microvessels during RUPP in late pregnancy.