Endothelial caveolar subcellular domain regulation of endothelial nitric oxide synthase

Ramadoss, Jayanth; Pastore, Mayra B.; Magness, Ronald R.

doi:10.1111/1440-1681.12136

Cited by 32 publications

(45 citation statements)

References 94 publications

(111 reference statements)

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“…Consistent with previous reports [17, 18, 98, 99, 118–120 ], we have recently shown that uterine artery endothelium (UAendo) total eNOS was elevated during the follicular phase and pregnancy [6]. The reported stimulatory phosphorylation site serine 635 (S635), an index of enzyme activity in UAendo [121, 122 ], was also elevated by pregnancy suggesting that both expression capacity and activity of eNOS are increased to accommodate increases in UBF. Additionally, we reported a pregnancy-associated adaptation in nonreproduc-tive OAendo which showed increases in both P 635 eNOS and total eNOS [6], the latter confirming our previous observation [18].…”

Section: Pregnancy-induced Changes In Cell-signalingsupporting

confidence: 85%

Gap Junction Regulation of Vascular Tone: Implications of Modulatory Intercellular Communication During Gestation

Ampey

Morschauser

Lampe

et al. 2014

Advances in Experimental Medicine and Biology

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In the vasculature, gap junctions (GJ) play a multifaceted role by serving as direct conduits for cell–cell intercellular communication via the facilitated diffusion of signaling molecules. GJs are essential for the control of gene expression and coordinated vascular development in addition to vascular function. The coupling of endothelial cells to each other, as well as with vascular smooth muscle cells via GJs, plays a relevant role in the control of vasomotor tone, tissue perfusion and arterial blood pressure. The regulation of cell-signaling is paramount to cardiovascular adaptations of pregnancy. Pregnancy requires highly developed cell-to-cell coupling, which is affected partly through the formation of intercellular GJs by Cx43, a gap junction protein, within adjacent cell membranes to help facilitate the increase of uterine blood flow (UBF) in order to ensure adequate perfusion for nutrient and oxygen delivery to the placenta and thus the fetus. One mode of communication that plays a critical role in regulating Cx43 is the release of endothelial-derived vasodilators such as prostacyclin (PGI2) and nitric oxide (NO) and their respective signaling mechanisms involving second messengers (cAMP and cGMP, respectively) that are likely to be important in maintaining UBF. Therefore, the assertion we present in this review is that GJs play an integral if not a central role in maintaining UBF by controlling rises in vasodilators (PGI2 and NO) via cyclic nucleotides. In this review, we discuss: (1) GJ structure and regulation; (2) second messenger regulation of GJ phosphorylation and formation; (3) pregnancy-induced changes in cell-signaling; and (4) the role of uterine arterial endothelial GJs during gestation. These topics integrate the current knowledge of this scientific field with interpretations and hypotheses regarding the vascular effects that are mediated by GJs and their relationship with vasodilatory vascular adaptations required for modulating the dramatic physiological rises in uteroplacental perfusion and blood flow observed during normal pregnancy.

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Section: Pregnancy-induced Changes In Cell-signalingsupporting

confidence: 85%

Gap Junction Regulation of Vascular Tone: Implications of Modulatory Intercellular Communication During Gestation

Ampey

Morschauser

Lampe

et al. 2014

Advances in Experimental Medicine and Biology

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“…These results suggest that a defect in EC is responsible for decreased NO bioavailability. In blood vessels, NO is produced by endothelial NO synthase (eNOS), the activity of which is regulated by Ca 2+ /calmodulin, binding of regulatory cofactors and posttranslational modifications including phosphorylation of Ser1177 which sensitizes eNOS to Ca 2 + , stimulating NO production 36–38 . To determine whether decreased eNOS activity is responsible for decreased NO production in Rap1b-deficient ECs, we examined agonist-induced phosphorylation of eNOS at Ser1177 39 .…”

Section: Resultsmentioning

confidence: 99%

Rap1b in Smooth Muscle and Endothelium Is Required for Maintenance of Vascular Tone and Normal Blood Pressure

Lakshmikanthan

Zieba

et al. 2014

ATVB

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Objective Small GTPase Rap1b controls several basic cellular phenomena and its deletion in mice leads to several cardiovascular defects, including impaired adhesion of blood cells and defective angiogenesis. We found that Rap1b knockout (Rap1b−/−) mice develop cardiac hypertrophy and hypertension. Therefore, we examined the function of Rap1b in regulation of blood pressure. Approach and Results Rap1b−/− mice developed cardiac hypertrophy and elevated blood pressure, but maintained a normal heart rate. Correcting elevated blood pressure with losartan, an angiotensin II type I receptor alleviated cardiac hypertrophy in Rap1b−/− mice, suggesting a possibility that cardiac hypertrophy develops secondary to hypertension. The indices of renal function and plasma renin activity were normal in Rap1b−/− mice. Ex vivo, we examined whether the effect of Rap1b-deletion on smooth muscle (SM)-mediated vessel contraction and endothelium-dependent vessel dilation, two major mechanisms controlling basal vascular tone, were the basis for the hypertension. We found increased contractility upon stimulation with a thromboxane analogue or Angiotensin II or phenylephrine along with increased inhibitory phosphorylation of myosin phosphatase under basal conditions consistent with elevated basal tone and the observed hypertension. cAMP-dependent-relaxation in response to Rap1 activator, Epac, was decreased in vessels from Rap1b−/− mice. Defective endothelial release of dilatory nitric oxide (NO) in response to elevated blood flow leads to hypertension. We found that NO-dependent vasodilation was significantly inhibited in Rap1b-deficient vessels. Conclusion This is the first report to indicate that Rap1b in both SM and endothelium plays a key role in maintaining blood pressure by controlling normal vascular tone.

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“…The synthesis of NO is regulated by eNOS activation in the heart [45]. The agonistinduced dephosphorylation of eNOS-Thr 495 in the calmodulin-binding domain is entirely Ca 2+ -dependent [42,46].…”

Section: The Effects Of Agiv On the Pi3k/akt/enos Signaling Pathwaymentioning

confidence: 99%

Astragaloside IV Improves Vasodilatation Function by Regulating the PI3K/Akt/eNOS Signaling Pathway in Rat Aorta Endothelial Cells

et al. 2018

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Coronary heart disease (CHD) remains a major public health burden. Endothelial-dependent coronary artery vasoreactivity is a significant indicator of vascular function. Endothelial dysfunction is characterized by decreased nitric oxide (NO) bioavailability and predicts late cardiovascular events. Astragaloside IV (AGIV) is the main active component of the herb Astragalus membranaceus. Although it shows a significant protective effect against vascular endothelial dysfunction, the mechanisms of AGIV promoting the vascular dilation have not been elucidated. This study investigated the vasodilator effect of AGIV on rat aortic rings and the underlying effect of AGIV via the PI3K/Akt/eNOS signaling pathway. We measured the relaxation of isolated RARs after different concentrations of AGIV treatment. Rat aorta endothelial cells were cultured with different doses of AGIV, dimethylsulfoxide, and NG-nitro L-arginine methyl ester. The expression of phosphorylated (p)-Akt and -endothelial nitric oxide synthase (p-eNOS) were tested by Western blot analysis. The messenger (m)RNA expression of eNOS was quantified by real-time polymerase chain reaction. AGIV exerted a vasodilator effect on the aortic rings and increased the NO content in a concentration-dependent manner. The vasorelaxation was suppressed by an eNOS inhibitor. AGIV regulated the PI3K/Akt/eNOS signaling pathway via phosphorylation of Akt at Ser⁴⁷³ and dephosphorylation of eNOS at Thr⁴⁹⁵. The mRNA expression of eNOS was remarkably upregulated by AGIV. AGIV significantly induced the dilation of the aortic rings, leading to the vasodilator response by enhancing the eNOS release via the PI3K/Akt/eNOS signaling pathway.

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Endothelial caveolar subcellular domain regulation of endothelial nitric oxide synthase

Cited by 32 publications

References 94 publications

Gap Junction Regulation of Vascular Tone: Implications of Modulatory Intercellular Communication During Gestation

Gap Junction Regulation of Vascular Tone: Implications of Modulatory Intercellular Communication During Gestation

Rap1b in Smooth Muscle and Endothelium Is Required for Maintenance of Vascular Tone and Normal Blood Pressure

Astragaloside IV Improves Vasodilatation Function by Regulating the PI3K/Akt/eNOS Signaling Pathway in Rat Aorta Endothelial Cells

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