Enhanced endothelin receptor type <scp>B</scp>‐mediated vasodilation and underlying [<scp><scp>Ca<sup>2+</sup></scp></scp>]<sub>i</sub> in mesenteric microvessels of pregnant rats

Mazzuca, M; Dang, Yiping; Khalil, Raouf A.

doi:10.1111/bph.12225

Cited by 25 publications

(43 citation statements)

References 93 publications

(134 reference statements)

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“…In addition, our previous studies in the aorta, carotid artery, and renal artery of virgin rats confirmed that ACh-induced relaxation was associated with increased NO production and was inhibited by the NOS inhibitor L-NAME (72). In contrast, in the mesenteric artery, a large portion of ACh-induced relaxation remained in the presence of L-NAME and the COX inhibitor indomethacin and was abolished by the K ϩ channel blocker TEA, suggesting a role of a hyperpolarization pathway (49,51). E 2 induces vasodilation through genomic and nongenomic endothelium-dependent and endothelium-independent pathways (53,64).…”

Section: Pregnancy-and E 2 /Er-related Adaptations In Vascular Functionmentioning

confidence: 64%

“…We have previously reported differences in the sensitivity of the ACh relaxation response to the NOS blocker L-NAME, COX inhibitor indomethacin, and the hyperpolarization pathway in different vascular beds of virgin rats (72) and in mesenteric vessels of virgin versus pregnant rats (49). In the present study, we assessed the role of endothelial vasodilators in ER agonist-induced relaxation of blood vessels of pregnant rats.…”

Section: Bp Plasma E 2 Body Weight and Tissue Weightmentioning

confidence: 85%

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Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy

Mata

Reslan

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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RA. Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy. Am J Physiol Heart Circ Physiol 309: H1679 -H1696, 2015. First published September 25, 2015 doi:10.1152/ajpheart.00532.2015.-Normal pregnancy is associated with adaptive hemodynamic, hormonal, and vascular changes, and estrogen (E 2) may promote vasodilation during pregnancy; however, the specific E 2 receptor (ER) subtype, post-ER signaling mechanism, and vascular bed involved are unclear. We tested whether pregnancy-associated vascular adaptations involve changes in the expression/ distribution/activity of distinct ER subtypes in a blood vessel-specific manner. Blood pressure (BP) and plasma E 2 were measured in virgin and pregnant (day 19) rats, and the thoracic aorta, carotid artery, mesenteric artery, and renal artery were isolated for measurements of ER␣, ER␤, and G protein-coupled receptor 30 [G protein-coupled ER (GPER)] expression and tissue distribution in parallel with relaxation responses to E 2 (all ERs) and the specific ER agonist 4,4=,4Љ-(4-propyl-[1H]-pyrazole-1,3,5-triyl)-tris-phenol (PPT; ER␣), diarylpropionitrile (DPN; ER␤), and G1 (GPER). BP was slightly lower and plasma E 2 was higher in pregnant versus virgin rats. Western blots revealed increased ER␣ and ER␤ in the aorta and mesenteric artery and GPER in the aorta of pregnant versus virgin rats. Immunohistochemistry revealed that the increases in ERs were mainly in the intima and media. In phenylephrineprecontracted vessels, E 2 and PPT caused relaxation that was greater in the aorta and mesenteric artery but similar in the carotid and renal artery of pregnant versus virgin rats. DPN-and G1-induced relaxation was greater in the mesenteric and renal artery than in the aorta and carotid artery, and aortic relaxation to G1 was greater in pregnant versus virgin rats. The nitric oxide synthase inhibitor N -nitro-L-arginine methyl ester with or without the cyclooxygenase inhibitor indomethacin with or without the EDHF blocker tetraethylammonium or endothelium removal reduced E 2, PPT, and G1-induced relaxation in the aorta of pregnant rats, suggesting an endothelium-dependent mechanism, but did not affect E 2-, PPT-, DPN-, or G1-induced relaxation in other vessels, suggesting endothelium-independent mechanisms. E 2, PPT, DPN, and G1 caused relaxation of Ca 2ϩ entry-dependent KCl contraction, and the effect of PPT was greater in the mesenteric artery of pregnant versus virgin rats. Thus, during pregnancy, an increase in ER␣ expression in endothelial and vascular smooth muscle layers of the aorta and mesenteric artery is associated with increased ER␣-mediated relaxation via endothelium-derived vasodilators and inhibition of Ca 2ϩ entry into vascular smooth muscle, supporting a role of aortic and mesenteric arterial ER␣ in pregnancyassociated vasodilation. GPER may contribute to aortic relaxation while enhanced ER␤ expression could mediate other genomic vascular effects during pregnancy.

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Section: Pregnancy-and E 2 /Er-related Adaptations In Vascular Functionmentioning

confidence: 64%

Section: Bp Plasma E 2 Body Weight and Tissue Weightmentioning

confidence: 85%

Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy

Mata

Reslan

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…Our laboratory has also shown that VSM contraction and [Ca 2ϩ ] i are reduced in renal arterial VSM cells of Preg rats (60). Also, endothelin-1-induced vasoconstriction and [Ca 2ϩ ] i are reduced in pressurized mesenteric microvessels of Preg compared with virgin rats (53). Although several studies have examined the pregnancy-related changes in arterial function and contraction mechanism, little is known regarding the changes in venous function during pregnancy.…”

Section: This Study Demonstrates Significant Reduction In Venous Funcmentioning

confidence: 98%

“…In addition, activation of protein kinase C (PKC) (30,38,42,80) or Rho kinase (ROCK) may play a role in the regulation of VSM contraction by increasing the [Ca 2ϩ ] i sensitivity of the contractile proteins (28,29,45,47,84). Several studies have also examined pregnancy-related changes in vascular reactivity in different arterial preparations from various species (15,17,31,36,41,53,60). Our laboratory has shown that aortic contraction is reduced in pregnant (Preg) compared with virgin rats (15,36,41,87).…”

Section: This Study Demonstrates Significant Reduction In Venous Funcmentioning

confidence: 99%

Pregnancy-associated adaptations in [Ca²⁺]_i-dependent and Ca²⁺sensitization mechanisms of venous contraction: implications in pregnancy-related venous disorders

Xia

Khalil

2016

American Journal of Physiology-Heart and Circulatory Physiology

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THE VENOUS SYSTEM IS COMPOSED of an intricate network of peripheral and conduit veins, as well as superficial and deep veins. The combined work of unidirectional valves, skeletal muscle contraction, and vein wall constriction ensures antegrade blood flow toward the heart and thereby maintain adequate venous return and cardiac output (51, 69). Vein dysfunction could lead to venous disorders that range in severity from unsightly lower extremity varicose veins to chronic venous insufficiency, deep vein thrombosis, and venous thromboembolism (69). In addition to risk factors such as diabetes, obesity, smoking, and age (3, 76), women may show greater incidence of varicose veins and chronic venous insufficiency than men (3,5,8,82). Also, our experimental studies showed decreased contraction in female vs. male rat inferior vena cava (IVC) (70,93). Among females, some premenopausal women may suffer from pelvic congestion syndrome, a poorly understood disorder of the pelvic venous circulation characterized by pelvic varicosities and pain worsened by prolonged standing, coitus, and menstruation (7). Importantly, the severity of pelvic congestion syndrome (7) and the risk of varicose veins (2,3,8,83,96), superficial and deep vein thrombosis, and venous thromboembolism increase during the course of pregnancy (9,39,50,66,92). In addition to blood hypercoagulability (33), changes in the vein wall mechanics and venous stasis (83) could play a role in pregnancy-related venous disorders. To understand the mechanisms involved in pregnancy-associated venous disorders, it is imperative to understand the cellular mechanisms regulating vascular function during normal pregnancy.Most of our knowledge regarding the cellular mechanisms of vascular contraction and the pregnancy-associated changes in vascular function comes from studies in arteries. Studies in various arterial preparations have suggested that increases in intracellular free Ca 2ϩ concentration ([Ca 2ϩ ] i ) due to initial Ca 2ϩ release from the intracellular stores and maintained Ca 2ϩ entry from the extracellular space are major determinants of

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“…Whereas ETAR is known primarily for its role and expression in the underlying smooth muscle vascular layer in blood vessels, recent reports have highlighted its expression and function in endothelial cells as well, including a role in the secretion of ET1, regulation of intracellular calcium levels, and protective effects against hypoxia-induced cellular injury (1,4,25,39,41). Recently, a study examined the role of ETBR in pregnant rats, which observed enhanced ETBR-mediated microvascular relaxation compared with virgin rats (28). In a follow-up study, the same group used a rodent model of hypertensive pregnancy (reduction of uteroplacental perfusion pressure rats) and determined that ET1-induced constriction of microvessels was enhanced vs. normal pregnant rats, which was attributed to ETBR disruption/downregulation (29).…”

Section: A T 1 R E T a R E T B Rmentioning

confidence: 99%

Microvascular endothelial cells from preeclamptic women exhibit altered expression of angiogenic and vasopressor factors

Lee

Nevo

2016

American Journal of Physiology-Heart and Circulatory Physiology

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Enhanced endothelin receptor type B‐mediated vasodilation and underlying [Ca²⁺]_i in mesenteric microvessels of pregnant rats

Cited by 25 publications

References 93 publications

Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy

Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy

Pregnancy-associated adaptations in [Ca²⁺]_i-dependent and Ca²⁺sensitization mechanisms of venous contraction: implications in pregnancy-related venous disorders

Microvascular endothelial cells from preeclamptic women exhibit altered expression of angiogenic and vasopressor factors

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Enhanced endothelin receptor type B‐mediated vasodilation and underlying [Ca2+]i in mesenteric microvessels of pregnant rats

Cited by 25 publications

References 93 publications

Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy

Adaptive increases in expression and vasodilator activity of estrogen receptor subtypes in a blood vessel-specific pattern during pregnancy

Pregnancy-associated adaptations in [Ca2+]i-dependent and Ca2+sensitization mechanisms of venous contraction: implications in pregnancy-related venous disorders

Microvascular endothelial cells from preeclamptic women exhibit altered expression of angiogenic and vasopressor factors

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Enhanced endothelin receptor type B‐mediated vasodilation and underlying [Ca²⁺]_i in mesenteric microvessels of pregnant rats

Pregnancy-associated adaptations in [Ca²⁺]_i-dependent and Ca²⁺sensitization mechanisms of venous contraction: implications in pregnancy-related venous disorders