Single-Cell Analysis Identify Transcription Factor BACH1 as a Master Regulator Gene in Vascular Cells During Aging.

Fei Ge,Mengping Jia,Dan Meng,Elena Osto,Jieyu Guo,Qing Jing,Xinhong Wang,Yue Qin,Xiangxiang Wei,Qi Pan,Lindi Jiang,Xiuling Zhi,Chengchao Ruan

doi:10.3389/fcell.2021.786496

Abstract

Vascular aging is a potent driver of cardiovascular and cerebrovascular diseases. Vascular aging features cellular and functional changes, while its molecular mechanisms and the cell heterogeneity are poorly understood. This study aims to 1) explore the cellular and molecular properties of aged cardiac vasculature in monkey and mouse and 2) demonstrate the role of transcription factor BACH1 in the regulation of endothelial cell (EC) senescence and its mechanisms. Here we analyzed published single-cell RNA sequencing (scRNA-seq) data from monkey coronary arteries and aortic arches and mouse hearts. We revealed that the gene expression of YAP1, insulin receptor, and VEGF receptor 2 was downregulated in both aged ECs of coronary arteries’ of monkey and aged cardiac capillary ECs of mouse, and proliferation-related cardiac capillary ECs were significantly decreased in aged mouse. Increased interaction of ECs and immunocytes was observed in aged vasculature of both monkey and mouse. Gene regulatory network analysis identified BACH1 as a master regulator of aging-related genes in both coronary and aorta ECs of monkey and cardiac ECs of mouse. The expression of BACH1 was upregulated in aged cardiac ECs and aortas of mouse. BACH1 aggravated endothelial cell senescence under oxidative stress. Mechanistically, BACH1 occupied at regions of open chromatin and bound to CDKN1A (encoding for P21) gene enhancers, activating its transcription in senescent human umbilical vein endothelial cells (HUVECs). Thus, these findings demonstrate that BACH1 plays an important role in endothelial cell senescence and vascular aging.

Highlights

Aging is a major and independent risk factor for the occurrence of cardiovascular and cerebrovascular disease (Camici et al, 2015)
We identified nine clusters of different cell types, including ECs, SMCs, epicardial cells (EPIs), adventitial fibroblasts (AFs), and immune cells (IMMs) (Figure 1A)
We revealed an increased interaction of ECs and immunocytes in aged vasculature of both monkeys and mice, whereas proliferation-related cardiac capillary ECs were significantly decreased in the heart of aged mouse

Summary

Introduction

Aging is a major and independent risk factor for the occurrence of cardiovascular and cerebrovascular disease (Camici et al, 2015). Vascular aging is associated with multiple disarrangements including oxidative stress, mitochondrial dysfunction, impaired resistance to molecular stressors, and chronic low-grade inflammation (Ungvari et al, 2018). Many of these observations arise from aging modeling in mice or rats, but appraisal of interspecies differences in a model closer to humans is required in a translational view (Ungvari et al, 2018). Defining the signatures of aging responses in the vasculature among different species, including monkeys, is essential to elucidate the regulatory mechanisms of vascular aging with clinical relevance

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