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DEVELOPMENTAL PHYSIOLOGY AND PREGNANCY

Differential [Ca²⁺]_i signaling of vasoconstriction in mesenteric microvessels of normal and reduced uterine perfusion pregnant rats

Division of Vascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts

Submitted 20 June 2008 ; accepted in final form 1 October 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 Ca²⁺ is a major determinant of vascular contraction, we hypothesized that the intracellular free calcium concentration ([Ca²⁺]_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 [Ca²⁺]_i (presented as fura 2 340/380 ratio). Basal [Ca²⁺]_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 [Ca²⁺]_i. KCl caused similar peak vasoconstriction and [Ca²⁺]_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 ([Ca²⁺]_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 [Ca²⁺]_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 [Ca²⁺]_i signal of vasoconstriction and the leftward shift in the [Ca²⁺]_i-vasoconstriction relationship in microvessels of RUPP compared with Norm-Preg rats suggest activation of [Ca²⁺]_i sensitization pathway(s). The similarity in vasoconstriction in RUPP and Norm-Preg rats suggests that such a [Ca²⁺]_i sensitization pathway(s) may also provide a feedback effect on Ca²⁺ mobilization/homeostatic mechanisms to protect against excessive vasoconstriction in systemic microvessels during RUPP in late pregnancy.

resistance vessels; vascular smooth muscle; intracellular free calcium concentration; preeclampsia