A novel role of VEPH1 in regulating AoSMC phenotypic switching.
Xiaofeng ShiCaiming XuYongqi LiHan WangWei MaYu TianHaifeng YangLei LiPublished in: Journal of cellular physiology (2020)
Abdominal aortic aneurysm (AAA) is a potentially lethal disease featured by focal dilatation in the aorta. The transition of vascular smooth muscle cells (SMCs) from a contractile/differentiated to a synthetic/dedifferentiated phenotype is considered to contribute to AAA formation and expansion. Our previous gene microarray data showed that Ventricular Zone Expressed PH Domain Containing 1 (VEPH1) expression increased in angiotensin II (Ang II)-infused aortic tissues. This study was thus performed to further explore the role of VEPH1. Herein, we first demonstrate that VEPH1 increases in the SMCs of Ang II-treated abdominal aortas. As in vivo, Ang II also upregulated VEPH1 expression in cultured hAoSMCs. The dedifferentiation of human aortic SMCs (hAoSMCs) was induced by a 24-hr stimulation of Ang II (1 μM)-the expression of contractile SMC markers, MYH11 and α-smooth muscle actin (α-SMA) decreased and that of synthetic markers, proliferating cell nuclear antigen and Vimentin increased. Inhibition of VEPH1 prevented Ang II-induced pathological dedifferentiation of hAoSMCs as indicated by the restored expression of MYH11 and α-SMA. In contrast, the forced overexpression of VEPH1 aggravated Ang II's effects. Furthermore, we demonstrated that VEPH1 and transforming growth factor-β1 (TGF-β1), a key regulator responsible for vascular SMC differentiation, negatively regulated each other's transcription. In contrast to VEPH1 silencing, its overexpression inhibited recombinant TGF-β1-induced increases in MYH11 and α-SMA and suppressed Smad3 phosphorylation and nuclear accumulation. Collectively, our study demonstrates that VEPH1 elevation promotes the synthetic phenotype switching of AoSMCs and suppressed the TGF-β1/Smad3 signaling pathway. Identification of VEPH1 as a pathogenic molecule for AAA formation provides novel insights into this disease.
Keyphrases
- angiotensin ii
- transforming growth factor
- vascular smooth muscle cells
- epithelial mesenchymal transition
- angiotensin converting enzyme
- poor prognosis
- smooth muscle
- signaling pathway
- transcription factor
- endothelial cells
- cell proliferation
- left ventricular
- magnetic resonance
- hypertrophic cardiomyopathy
- skeletal muscle
- abdominal aortic aneurysm
- binding protein
- high glucose
- heart failure
- magnetic resonance imaging
- gene expression
- pulmonary artery
- dna methylation
- single cell
- computed tomography
- cell therapy
- pulmonary hypertension
- pi k akt
- oxidative stress
- induced apoptosis
- atrial fibrillation
- pulmonary arterial hypertension
- endoplasmic reticulum stress
- genome wide analysis