Differential [Ca2+]i signaling of vasoconstriction in mesenteric microvessels of normal and reduced uterine perfusion pregnant rats.
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.
Chen
Wensheng
W
Division of Vascular Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA.
Khalil
Raouf A
RA
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D046110:Hypertension, Pregnancy-Induced / Q000378:metabolism / Q000503:physiopathology*; D008098:Litter Size; D008643:Mesentery / Q000098:blood supply*; D008833:Microcirculation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013152:Splanchnic Circulation / Q000187:drug effects; D014599:Uterus / Q000098:blood supply*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D019332:Endothelin-1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010656:Phenylephrine; D011189:Potassium Chloride