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Caveolin?1 modulates hypertensive vascular remodeling via regulation of the Notch pathway.

ABSTRACT: Hypertension is one of the critical risk factors of cerebrovascular disease. Caveolin?1 (Cav?1) has been suggested to be involved in the development of hypertension; however, the underlying mechanism remains largely unknown. Therefore, the present study aimed to investigate the mechanism underlying Cav?1 in hypertension. In the present study, the hypertension model was induced by infusion of angiotensin II (Ang?II) in rats. Cell Counting Kit?8 assay was used to detect the viability of human umbilical vein endothelial cells (HUVECs). Flow cytometry was used to determine the apoptosis of HUVECs. Transmission electron microscopy was utilized to address the thickness of the vessel walls. Reverse transcription?quantitative PCR, western blotting and immunofluorescence staining were used to assess the mechanism of cav?1/Notch1 involved in hypertensive vascular remodeling. In the present study, an Ang?II?induced hypertension model was successfully established in rats. With this model, it was found that the expression levels of cav?1 and Notch1 were significantly increased in brain tissues in the hypertension group compared with the sham?operated group. In cultured HUVECs, knockdown of cav?1 regulated Ang?II?induced HUVEC viability and apoptosis, and modulated hypertensive vascular remodeling, which was mediated by the Notch pathway. The data of the present study demonstrated that the cav?1/Notch signaling plays an important role in the regulation of Ang?II?induced hypertension and vascular remodeling.

SUBMITTER: Wang Q

PROVIDER: S-EPMC7533525 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Caveolin‑1 modulates hypertensive vascular remodeling via regulation of the Notch pathway.

Wang Qian Q Lao Minxi M Xu Zhen Z Ding Meilin M Guo Shaolei S Li Ling L

Molecular medicine reports 20200914 5

Hypertension is one of the critical risk factors of cerebrovascular disease. Caveolin‑1 (Cav‑1) has been suggested to be involved in the development of hypertension; however, the underlying mechanism remains largely unknown. Therefore, the present study aimed to investigate the mechanism underlying Cav‑1 in hypertension. In the present study, the hypertension model was induced by infusion of angiotensin II (Ang‑II) in rats. Cell Counting Kit‑8 assay was used to detect the viability of human umbi ...[more]

PMID: 33000233

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Project description:The Notch signaling pathway participates in pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis. Astragaloside IV (AS‑IV) is an effective antiproliferative treatment for vascular diseases. The present study aimed to investigate the protective effects and mechanisms underlying AS‑IV on hypoxia‑induced PASMC proliferation and pulmonary vascular remodeling in pulmonary arterial hypertension (PAH) model rats. Rats were divided into the following four groups: i) normoxia; ii) hypoxia (10% O2); iii) treatment, hypoxia + intragastrical administration of AS‑IV (2 mg/kg) daily for 28 days; and iv) DAPT, hypoxia + AS‑IV treatment + subcutaneous administration of DAPT (10 mg/kg) three times daily. The effects of AS‑IV treatment on the development of hypoxia‑induced PAH, right ventricle (RV) hypertrophy and pulmonary vascular remodeling were examined. Furthermore, PASMCs were treated with 20 µmol/l AS‑IV under hypoxic conditions for 48 h. To determine the effect of Notch signaling in vascular remodeling and the potential mechanisms underlying AS‑IV treatment, 5 mmol/l γ‑secretase inhibitor [N‑[N‑(3,5‑difluorophenacetyl)‑L‑alanyl]‑S‑phenylglycine t‑butyl ester (DAPT)] was used. Cell viability and apoptosis were determined by performing the MTT assay and flow cytometry, respectively. Immunohistochemistry was conducted to detect the expression of proliferating cell nuclear antigen (PCNA). Moreover, the mRNA and protein expression levels of Notch‑3, Jagged‑1, hes family bHLH transcription factor 5 (Hes‑5) and PCNA were measured via reverse transcription‑quantitative PCR and western blotting, respectively. Compared with the normoxic group, hypoxia‑induced PAH model rats displayed characteristics of PAH and RV hypertrophy, whereas AS‑IV treatment alleviated PAH and prevented RV hypertrophy. AS‑IV also inhibited hypoxia‑induced pulmonary vascular remodeling, as indicated by reduced wall thickness and increased lumen diameter of pulmonary arterioles, and decreased muscularization of distal pulmonary vasculature in hypoxia‑induced PAH model rats. Compared with normoxia, hypoxia promoted PASMC proliferation in vitro, whereas AS‑IV treatment inhibited hypoxia‑induced PASMC proliferation by downregulating PCNA expression in vitro and in vivo. In hypoxia‑treated PAH model rats and cultured PASMCs, AS‑IV treatment reduced the expression levels of Jagged‑1, Notch‑3 and Hes‑5. Furthermore, Notch signaling inhibition via DAPT significantly inhibited the pulmonary vascular remodeling effect of AS‑IV in vitro and in vivo. Collectively, the results indicated that AS‑IV effectively reversed hypoxia‑induced pulmonary vascular remodeling and PASMC proliferation via the Notch signaling pathway. Therefore, the present study provided novel insights into the mechanism underlying the use of AS‑IV for treatment of vascular diseases, such as PAH.

Project description:Objective- Flow patterns differentially regulate endothelial cell phenotype, with laminar flow promoting vasodilation and disturbed flow promoting endothelial proinflammatory activation. CSE (cystathionine ?-lyase), a major source of hydrogen sulfide (H2S) in endothelial cells, critically regulates cardiovascular function, by both promoting vasodilation and reducing endothelial activation. Therefore, we sought to investigate the role of CSE in the endothelial response to flow. Approach and Results- Wild-type C57Bl/6J and CSE knockout ( CSE-/-) mice underwent partial carotid ligation to induce disturbed flow in the left carotid. In addition, endothelial cells isolated from wild-type and CSE -/- mice were exposed to either laminar or oscillatory flow, an in vitro model of disturbed flow. Interestingly, laminar flow significantly reduced CSE expression in vitro, and only disturbed flow regions show discernable CSE protein expression in vivo, correlating with enhanced H2S production in wild-type C57BL/6J but not CSE-/- mice. Lack of CSE limited disturbed flow-induced proinflammatory gene expression (ICAM-1[intercellular adhesion molecule 1], VCAM-1 [vascular cell adhesion molecular 1]) and monocyte infiltration and CSE-/- endothelial cells showed reduced NF-?B (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and proinflammatory gene expression in response to oscillatory flow in vitro. In addition, CSE-/- mice showed reduced inward remodeling after partial carotid ligation. CSE-/- mice showed elevated vascular nitrite levels (measure of nitric oxide [NO]) in the unligated carotids, suggesting an elevation in baseline NO production, and the NO scavenger 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide normalized the reduced inward remodeling, but not inflammation, of ligated carotids in CSE-/- mice. Conclusions- CSE expression in disturbed flow regions critically regulates both endothelial activation and flow-dependent vascular remodeling, in part through altered NO availability.

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Caveolin?1 modulates hypertensive vascular remodeling via regulation of the Notch pathway.

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Caveolin‑1 modulates hypertensive vascular remodeling via regulation of the Notch pathway.

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