Enhanced contractility in pregnancy is associated with augmented TRPC3, L-type, and T-type voltage-dependent calcium channel function in rat uterine radial artery

Abstract

In pregnancy, ␣-adrenoceptor-mediated vasoconstriction is augmented in uterine radial arteries and is accompanied by underlying changes in smooth muscle (SM) Ca 2ϩ activity. This study aims to determine the Ca 2ϩ entry channels associated with altered vasoconstriction in pregnancy, with the hypothesis that augmented vasoconstriction involves transient receptor potential canonical type-3 (TRPC3) and L-and T-type voltage-dependent Ca 2ϩ channels. Immunohistochemistry showed TRPC3, L-type Ca v1.2 (as the ␣1C subunit), T-type Cav3.1 (␣1G), and Ca v3.2 (␣1H) localization to the uterine radial artery SM. Fluorescence intensity of TRPC3, Ca v1.2, and Cav3.2 was increased, and Ca v3.1 decreased in radial artery SM from pregnant rats. Western blot analysis confirmed increased TRPC3 protein expression in the radial artery from pregnant rats. Pressure myography incorporating pharmacological intervention to examine the role of these channels in uterine radial arteries showed an attenuation of phenylephrine (PE)-induced constriction with Pyr3 {1-[4-[(2,3,3-trichloro-1-oxo-2-propen-1-yl) amino]phenyl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid}-mediated TRPC3 inhibition or with nifedipine-mediated L-type channel block alone in vessels from pregnant rats; both effects of which were diminished in radial arteries from nonpregnant rats. Combined TRPC3 and L-type inhibition attenuated PE-induced constriction in radial arteries, and the residual vasoconstriction was reduced and abolished with T-type channel block with NNC 55-0396 in arteries from nonpregnant and pregnant rats, respectively. With SM Ca 2ϩ stores depleted and in the presence of PE, nifedipine, and NNC 55-0396, blockade of TRPC3 reversed PE-induced constriction. These data suggest that TRPC3 channels act synergistically with L-and T-type channels to modulate radial artery vasoconstriction, with the mechanism being augmented in pregnancy. vascular smooth muscle; TRPC3; voltage-dependent Ca 2ϩ channel; constriction IN PREGNANCY, remodeling of uterine radial resistance arteries is associated with altered vascular tone, underpinned by augmented sensitivity to constrictor stimuli (14,24,29,39,42,43), and elevated myogenic tone (11,14,20,31,39,54,57), with the latter being apparently related to placentation type. Regulation of vascular smooth muscle (SM) constriction is a primary determinant of vascular tone and is accompanied by changes in the intracellular SM [Ca 2ϩ ], modulated via the activity of ion channels, the sarcoplasmic reticulum Ca 2ϩ store, and the sensitivity of the contractile apparatus to intracellular [Ca 2ϩ ] (53). Calcium influx via voltage-dependent Ca 2ϩ channels (VDCC) and the nonvoltage-dependent channels from the transient receptor potential (TRP) family represent key pathways of intracellular Ca 2ϩ entry and Ca 2ϩ store refilling in the vasculature (47), with limited information on the role of these pathways in the uterine vasculature, and changes associated with pregnancy.TRP channels are a family of generally nonselective cation channels tha...

TRPC3 Overexpression Promotes the Progression of Inflammation-Induced Preterm Labor and Inhibits T Cell Activation

“…TRPCs as a subfamily of calcium channels have been increasingly concerned [13]. Senadheera et al found that increased TRPC3 can enhance the contractility of a pregnant uterus [6]. Their findings indicate that TRPC3 is likely a factor involved in the initiation of labor.…”

“…Transient receptor potential channels (TRPC) are a group of nonselective cation channels with six transmembrane spanning helices [5, 6]. Activation of TRPC leads to trans-sarcolemmal Ca 2+ influx to directly increase the intracellular Ca 2+ concentration; it can also lead to trans-sarcolemmal Na + influx to indirectly increase the intracellular Ca 2+ concentration [7].…”

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