Submitted on June 20, 2008
Revised on September 11, 2008
Accepted on October 1, 2008
Differential [Ca2+]i Signaling of Vasoconstriction in Mesenteric Microvessels of Normal and Reduced Uterine Perfusion Pregnant Rats
Wensheng Chen and Raouf A. Khalil1*
1 Brigham & Women's Hospital
* To whom correspondence should be addressed. E-mail: raouf_khalil{at}hms.harvard.edu.
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 [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 to Norm-Preg rats (0.82±0.03). Membrane depolarization by 96 mM KCl, phenylephrine (Phe, 10-5 M), angiotensin II (AngII, 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 and RUPP rats. Maximum vasoconstriction to Phe, AngII, and ET-1 was not significantly different between Norm-Preg and RUPP rats. In contrast, the initial Phe, AngII, and ET-1 induced 340/380 ratio ([Ca2+]i) was reduced in RUPP compared to Norm-Preg rats. Also, the [Ca2+]i-vasoconstriction relationship was similar in KCl-treated, but shifted to the left in Phe, AngII and ET-1 treated microvessels of RUPP compared to 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 to Norm-Preg rats suggest activation of [Ca2+]i sensitization pathway(s). The similarity in vasoconstriction in RUPP and Norm-Preg rats suggests that such [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.
