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Language：English   Publishing type：Book review, literature introduction, etc.  

During pregnancy, the renin-angiotensin system (RAS) plays an important role in regulating the markedly expanded circulating blood volume in the uteroplacental circulation. RAS is activated during normal pregnancy
however, blood pressure decreases from the 1st trimester to the 2nd trimester. Vascular responsiveness to angiotensin II (AngII) decreases early in pregnancy
on the other hand, pregnant women who subsequently develop PIH are exquisitely sensitive to the pressor effect of AngII. Interestingly. the maternal circulating RAS and the placental concentration of AngII receptor (ATR) are stable or reduced in PIH. The balance of expression between ATR subtype 1 (AT1) and 2 (AT2) is potentially important in the regulation of vascular tone during pregnancy. Increased AT1/AT2 may explain the loss of vascular refractoriness to AngII in the pathogenesis of PIH. Recently, endothelial progenitor cell (EPC) has been found in the peripheral blood of pregnant women. Although AngII stimulates EPC proliferation, the mobilization is inhibited in PIH. Impairment of EPC mobilization may contribute to insufficient regeneration of endothelium in the impaired utero-placental circulation of PIH. This review focuses on vascular endothelial dysfunction and the effect of RAS in the pathophysiology of PIH. © 2006 Bentham Science Publishers Ltd.

DOI： 10.2174/157340206778742575

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Language：English   Publisher：ELSEVIER SCIENCE INC  

Background: Activation of the renin-angiotensin system with increased levels of renin and angiotensin (Ang) 11 in pregnancy has been reported, but the vascular responsiveness to Ang II seems to be decreased, thereby keeping maternal blood pressure (BP) constant. We postulated that the balance of angiotensin type I (AT1) and angiotensin type 2 (AT2) receptor expression, which would exert antagonistic actions on vasoconstriction and cell growth, might control BP in pregnancy.
Methods: Using wild type (C57BL/6J), angiotensin type la (AT1a) receptor null and AT2 receptor null mice, we examined the changes in BP, expression and localization of AT I and AT2 receptors in placenta, umbilical cord, and uterus by immunohistochemical staining and urinary albumin measurement during pregnancy.
Results: Wild type mice did not show any significant change in BP throughout pregnancy. The BP in AT1a receptor null mice declined significantly in the second trimester of pregnancy, whereas BP in AT2 receptor null mice increased significantly in the third trimester. We did not observe any significant differences in albuminuria, litter size, or body weight of neonates among the three groups. Vascular smooth muscle cells in blood vessels of the umbilical cord and placenta specifically expressed AT2 receptors, which are minimally expressed in adult vessels. In contrast, AT1 receptors were dominantly expressed in the cytotrophoblast and chorionic plate as well as blood vessels in placenta and umbilical cord.
Conclusions: Our results suggested that disturbance of the balance of the AT1 and AT2 receptors could trigger pregnancy induced hypertension. (C) 2004 American Journal of Hypertension, Ltd.

DOI： 10.1016/j.amjhyper.2004.03.680

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Language：English   Publisher：ELSEVIER SCIENCE INC  

Objective: The normal suppression of vascular sensitivity to angiotensin II (Ang II) in pregnancy is lost in pregnancy-induced hypertension (PIH). To examine the mechanism, we investigated Ang II receptor subtype 1 (AT1R) and 2 (AT2R) expression in human umbilical vein endothelial cells (HUVEC) and vascular smooth muscle cells (VSMC).
Methods: The HUVEC and VSMC were incubated with serum from normal pregnant women and PIH patients for 0 to 12 h. The AT1R and AT2R mRNA were semi-quantified as the ratio to glyceraldehyde-3-phosphate dehydrogenase mRNA, using multiplex reverse transcription-polymerase chain reaction. The AT1R expression was also evaluated by immunocytochemistry.
Results: Serum from PIH patients significantly increased AT1R mRNA of HUVEC (1.48 +/- 0.44) after a 12-h incubation compared with that from normal pregnant women (0.25 +/- 0.14). On the other hand, AT2R mRNA of HUVEC incubated with serum from PIH patients (0.14 +/- 0.02) was significantly decreased compared with HUVEC incubated with serum from normal pregnant women (0.31 +/- 0.08). The AT1R mRNA of VSMC was significantly increased by serum from both PIH patients and normal pregnant women. The AT1R-to-AT2R mRNA ratio increased by serum from PIE patients was significantly reduced by anti-tumor necrosis factor-alpha (TNF-alpha) antibody (20 mug/mL). Valsartan (an AT1R antagonist, at 1 to 10 nmol/L) significantly increased AT2R mRNA of HUVEC. Also, immunocytochemistry demonstrated that endothelial AT1R expression was strongly increased by PIH sera and reduced by anti-TNF-alpha antibody.
Conclusions: Endothelial AT1R expression is increased and AT2R expression is decreased in PIH. The TNF-alpha is related to the pathogenesis of PIH by reduced AT2R mRNA through an increase of AT1R mRNA. (C) 2003 American Journal of Hypertension, Ltd.

DOI： 10.1016/j.amjhyper.2003.07.020

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

The present study explored the possibility that estrogen may enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT(1)) receptor blocker on neointima formation in vascular injury, and investigated the signaling mechanism involved in their actions. Polyethylene cuff placement around the femoral artery of mice induced neointima formation and increased bromodeoxyuridine (BrdU) incorporation into vascular smooth muscle cells. These changes were significantly smaller in female mice than in male mice. Ovariectomy enhanced neointima formation and BrdU incorporation in the injured artery, which were reversed by 17beta-estradiol (80 mug/kg per day) replacement. Treatment with a selective AT(1) receptor blocker, olmesartan (3 mg/kg per day), significantly inhibited neointima formation and BrdU incorporation, whereas the inhibitory effects of olmesartan were more marked in intact female mice than in male or ovariectomized mice. Phosphorylation of extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription (STAT) 1, and STAT3 was increased in the injured artery. These increases were significantly smaller in intact female mice than in male or ovariectomized mice. Olmesartan or estrogen attenuated the phosphorylation of ERK and STAT in the injured artery, whereas these inhibitory effects were greater in intact female mice. Lower doses of olmesartan (0.5 mg/kg per day) or 17beta-estradiol (20 mug/kg per day) did not influence neointima formation, BrdU incorporation, and ERK and STAT phosphorylation in ovariectomized mice, whereas coadministration of olmesartan and 17beta-estradiol at these doses attenuated these parameters. These results indicate that estrogen and an AT(1) receptor blocker synergistically attenuate vascular remodeling, which is at least partly via inhibition of ERK and STAT activity.

DOI： 10.1161/01.HYP.0000033466.05496.89

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Accumulating evidence suggests that estrogen exerts cardioprotective effects and protects against neointima formation in response to vascular injury in vivo, whereas angiotensin (Ang) II stimulation via the Ang II type 1 (AT(1)) receptor exaggerates vascular injury. We postulate that estrogen treatment antagonizes the AT(1) receptor-mediated growth-promoting effects in vascular smooth muscle cells (VSMCs). The present in vitro study was designed to explore this possibility and to establish the cellular mechanism whereby estrogen attenuates the growth of VSMCs. Primary cultures of VSMCs derived from male adult Sprague-Dawley rats express exclusively AT(1) receptors. Treatment with Ang II enhanced proliferation of VSMC and c-fos expression, whereas 17beta-estradiol (E2) attenuated these vasotrophic effects of Ang II. We also demonstrated that E2 attenuated AT(1) receptor-mediated extracellular signal-regulated kinase activation and that this effect of E2 was restored by pretreatment with vanadate or okadaic acid. Moreover, we demonstrated that E2 enhanced SHP-1 activity, rapidly reaching a peak after 3 minutes of E2 stimulation, whereas E2 transactivated mitogen-activated protein kinase phosphatase-1 expression, showing a peak after 60 minutes of E2 treatment. SHP-1 activation was not influenced by actinomycin D treatment, whereas E2-mediated mitogen-activated protein kinase phosphatase-1 expression was attenuated. Taken together, our results suggest a novel mechanism of vasoprotection by which estrogen antagonizes the effect of the AT(1) receptor via the activation and induction of phosphatases through nongenomic as well as genomic signaling.

DOI： 10.1161/hy1201.097197

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