Notch3 signalling and vascular remodelling in pulmonary arterial hypertension.

Hannah E Morris,Karla B Neves,Augusto C Montezano,Rhian M Touyz,Margaret R Maclean

doi:10.1042/cs20190835

Hannah E Morris, Karla B Neves + Show 3 more

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https://doi.org/10.1042/cs20190835

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Journal: Clinical Science	Publication Date: Dec 20, 2019
Citations: 72	License type: CC BY 4.0

Affiliation: University of Glasgow, University of Strathclyde

Abstract

Notch signalling is critically involved in vascular morphogenesis and function. Four Notch isoforms (Notch1–4) regulating diverse cellular processes have been identified. Of these, Notch3 is expressed almost exclusively in vascular smooth muscle cells (VSMCs), where it is critically involved in vascular development and differentiation. Under pathological conditions, Notch3 regulates VSMC switching between the contractile and synthetic phenotypes. Abnormal Notch3 signalling plays an important role in vascular remodelling, a hallmark of several cardiovascular diseases, including pulmonary arterial hypertension (PAH). Because of the importance of Notch3 in VSMC (de)differentiation, Notch3 has been implicated in the pathophysiology of pulmonary vascular remodelling in PAH. Here we review the current literature on the role of Notch in VSMC function with a focus on Notch3 signalling in pulmonary artery VSMCs, and discuss potential implications in pulmonary artery remodelling in PAH.

Highlights

Notch proteins are cell membrane receptors that mediate signalling between cells and play an important role in cell-to-cell communication [1]
The same effects were seen in a smooth muscle-specific RBP-Jκ knockout animal [128]. These findings suggest that absence of canonical Notch3 signalling in normal vascular smooth muscle cells (VSMCs) promotes development of heart failure in response to pressure overload, and pressure overload is an important feature in later stage pulmonary arterial hypertension (PAH)
Overexpression of miR-206 in hPASMCs increased expression of vascular smooth muscle differentiation markers calponin and α-smooth muscle actin (SMA), while reducing Notch3 expression, migration and proliferation [135]. These results suggest down-regulation of miR-206 in PAH may contribute to Notch3 up-regulation and the pro-proliferative/anti-apoptotic phenotype observed in patients

Summary

Introduction

Notch proteins are cell membrane receptors that mediate signalling between cells and play an important role in cell-to-cell communication [1]. Notch signalling can regulate expression of KLF5 which, unlike KLF4, causes VSMC proliferation and a synthetic phenotype, important in vascular remodelling in PAH, in hypoxia [67,68].

Results

Conclusion