Thromboxane Receptors in Smooth Muscle Promote Hypertension, Vascular Remodeling, and Sudden Death

Sparks, Matthew A.; Makhanova, Natalia; Griffiths, Robert; Snouwaert, John N.; Koller, Beverly H.; Coffman, Thomas M.

doi:10.1161/hypertensionaha.112.193250

Cited by 39 publications

(34 citation statements)

References 32 publications

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“…miR-31 also achieves its angiogenic role by targeting the receptor of TBXA2. TBXA2, which is a prostanoid, has received great attention because of its involvement in platelet function and the pathogenesis of many cardiovascular diseases, including atherosclerosis and hypertension, 55,56 via interaction with its specific receptor TBXA2R, a G proteincoupled receptor on endothelial cells. 26 TBXA2R signaling is able to inhibit VEGF-induced endothelial cell differentiation and migration.…”

Section: Discussionmentioning

confidence: 99%

“…TBXA2R in smooth muscle promotes angiotensin II-induced hypertension, vascular remodeling, and sudden death. 56 Recent experimental findings have indicated that synthetic TBXA2/prostaglandin receptor inhibitors seem to have potent antiplatelet activity with an antiatherosclerotic effect. Such activity has important implications especially when they are used to target clinical conditions associated with an increased production of prostanoids, such as CAD and diabetes mellitus.…”

Section: Discussionmentioning

confidence: 99%

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Deficiency of the MicroRNA-31–MicroRNA-720 Pathway in the Plasma and Endothelial Progenitor Cells From Patients With Coronary Artery Disease

Wang

Huang

et al. 2014

ATVB

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Objective-Defects in angiogenesis/vasculogenesis or vessel repair are major complications of coronary artery disease (CAD). Endothelial progenitor cells (EPCs) play a fundamental role in postnatal vascular repair and CAD. The role of microRNAs in CAD pathogenesis and their potential as biomarkers remain to be elucidated. Approach and Results-MicroRNA-31 (miR-31) level in both the plasma and EPCs of patients with CAD is found lower.miR-31 regulates EPC activities by targeting FAT atypical cadherin 4 and thromboxane A2 receptor, which show increased expression in CAD EPCs. Overexpressing miR-31 in CAD EPCs rescued their angiogenic and vasculogenic abilities both in vitro and in vivo. When exploring approaches to restore endogenous miR-31, we found that far-infrared treatment enhanced the expression of not only miR-31, but also miR-720 in CAD EPCs. miR-720, which was also decreased in EPCs and the plasma of patients with CAD, stimulated EPC activity by targeting vasohibin 1. The miR720-vasohibin 1 pair was shown to be downstream of FAT atypical cadherin 4, but not of thromboxane A2 receptor. FAT atypical cadherin 4 inhibited miR-720 expression via repression of the planar cell polarity signaling gene four-jointed box 1 (FJX1), which was required for miR-720 expression through a hypoxia-inducible factor 1, α subunit-dependent mechanism. Restoring miR-720 level strengthened activity of CAD EPCs. The miR-31-miR-720 pathway is shown critical to EPC activation and that downregulation of this pathway contributes to CAD pathogenesis. Circulating levels of miR-31, miR-720, and vasohibin 1 have the potential to allow early diagnosis of CAD and to act as prognosis biomarkers for CAD and other EPC-related diseases. In addition to the number of circulating EPCs present, the regulation of postnatal angiogenesis/vasculogenesis also depends on the activity of mobilized EPCs. 8 In addition to the effects of protein-coding genes, the expression of various different microRNAs (miRNAs, miRs) also plays a critical role in the clinical course of CAD. miRNAs are a class of endogenous, small, noncoding, single-stranded RNAs of ≈22 nucleotides in length. The mature miRNAs negatively regulate gene expression by targeting specific mRNAs for cleavage or translational repression. Detecting the levels of tissue miRNAs, as well as the levels of circulating miRNAs in body fluids, is considered to be a potential approach to identifying new disease biomarkers and novel drug targets. Conclusions-Manipulating9-11 Many proangiogenic and antiangiogenic miRNAs have been pinpointed. Examples such as miR-221 and miR-222, which are transcribed from the same miR-221/222 cluster, have been shown to be able to modulate the angiogenic properties of human umbilical vein endothelial cells by targeting c-Kit and endothelial NO synthase.12,13 miR-221/222 levels in EPCs are significantly higher in patients with CAD.14,15 miR-10a* and miR-21 are also known to modulate EPC senescence via the suppression of high-mobility group A2.16 miR-10b and miR-196b, on the cont...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Deficiency of the MicroRNA-31–MicroRNA-720 Pathway in the Plasma and Endothelial Progenitor Cells From Patients With Coronary Artery Disease

Wang

Huang

et al. 2014

ATVB

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“…Using the mTmG dual-reporter mouse line, 12 we have previously demonstrated robust green fluorescent protein fluorescence in the media of the aorta and throughout glomerular afferent arterioles in KISm22a-Cre-mTmG mice, confirming robust expression of Cre-recombinase in large arteries and resistance vessels. 13 To document efficient elimination of AT 1A receptors, we measured levels for AT 1A receptor mRNA by real-time quantitiative RT-PCR. Segments of the aorta were isolated from SMKO and control mice.…”

Section: Generation Of Mice With Cell-specific Deletion Of At 1 Recepmentioning

confidence: 99%

Vascular Type 1A Angiotensin II Receptors Control BP by Regulating Renal Blood Flow and Urinary Sodium Excretion

Sparks

Stegbauer

Chen

et al. 2015

Journal of the American Society of Nephrology

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Inappropriate activation of the type 1A angiotensin (AT 1A ) receptor contributes to the pathogenesis of hypertension and its associated complications. To define the role for actions of vascular AT 1A receptors in BP regulation and hypertension pathogenesis, we generated mice with cell-specific deletion of AT 1A receptors in smooth muscle cells (SMKO mice) using Loxp technology and Cre transgenes with robust expression in both conductance and resistance arteries. We found that elimination of AT 1A receptors from vascular smooth muscle cells (VSMCs) caused a modest (approximately 7 mmHg) yet significant reduction in baseline BP and exaggerated sodium sensitivity in mice. Additionally, the severity of angiotensin II (Ang II)-dependent hypertension was dramatically attenuated in SMKO mice, and this protection against hypertension was associated with enhanced urinary excretion of sodium. Despite the lower BP, acute vasoconstrictor responses to Ang II in the systemic vasculature were largely preserved (approximately 80% of control levels) in SMKO mice because of exaggerated activity of the sympathetic nervous system rather than residual actions of AT 1B receptors. In contrast, Ang II-dependent responses in the renal circulation were almost completely eliminated in SMKO mice (approximately 5%-10% of control levels). These findings suggest that direct actions of AT 1A receptors in VSMCs are essential for regulation of renal blood flow by Ang II and highlight the capacity of Ang II-dependent vascular responses in the kidney to effect natriuresis and BP control.

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“…22 It is broadly distributed throughout the body, with higher expression observed in the immune organs. 23 Thromboxane/TP has been implicated in allergic inflammation, 24 blood pressure regulation, 25 vascular remodeling, 26 and atherosclerosis. 27 TP receptor antagonists display multiple beneficial effects in cardiovascular diseases.…”

mentioning

confidence: 99%

Thromboxane Governs the Differentiation of Adipose-Derived Stromal Cells Toward Endothelial Cells In Vitro and In Vivo

Shen

Zuo

Wang

et al. 2016

Circulation Research

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Rationale: Autologous adipose-derived stromal cells (ASCs) offer great promise as angiogenic cell therapy for ischemic diseases. Because of their limited self-renewal capacity and pluripotentiality, the therapeutic efficacy of ASCs is still relatively low. Thromboxane has been shown to play an important role in the maintenance of vascular homeostasis. However, little is known about the effects of thromboxane on ASC-mediated angiogenesis. Objective: To explore the role of the thromboxane-prostanoid receptor (TP) in mediating the angiogenic capacity of ASCs in vivo. Methods and Results: ASCs were prepared from mouse epididymal fat pads and induced to differentiate into endothelial cells (ECs) by vascular endothelial growth factor. Cyclooxygenase-2 expression, thromboxane production, and TP expression were upregulated in ASCs on vascular endothelial growth factor treatment. Genetic deletion or pharmacological inhibition of TP in mouse or human ASCs accelerated EC differentiation and increased tube formation in vitro, enhanced angiogenesis in in vivo Matrigel plugs and ischemic mouse hindlimbs. TP deficiency resulted in a significant cellular accumulation of β-catenin by suppression of calpain-mediated degradation in ASCs. Knockdown of β-catenin completely abrogated the enhanced EC differentiation of TP-deficient ASCs, whereas inhibition of calpain reversed the suppressed angiogenic capacity of TP re-expressed ASCs. Moreover, TP was coupled with Gαq to induce calpain-mediated suppression of β-catenin signaling through calcium influx in ASCs. Conclusion: Thromboxane restrained EC differentiation of ASCs through TP-mediated repression of the calpain-dependent β-catenin signaling pathway. These results indicate that TP inhibition could be a promising strategy for therapy utilizing ASCs in the treatment of ischemic diseases.

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Thromboxane Receptors in Smooth Muscle Promote Hypertension, Vascular Remodeling, and Sudden Death

Cited by 39 publications

References 32 publications

Deficiency of the MicroRNA-31–MicroRNA-720 Pathway in the Plasma and Endothelial Progenitor Cells From Patients With Coronary Artery Disease

Deficiency of the MicroRNA-31–MicroRNA-720 Pathway in the Plasma and Endothelial Progenitor Cells From Patients With Coronary Artery Disease

Vascular Type 1A Angiotensin II Receptors Control BP by Regulating Renal Blood Flow and Urinary Sodium Excretion

Thromboxane Governs the Differentiation of Adipose-Derived Stromal Cells Toward Endothelial Cells In Vitro and In Vivo

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