Perivascular adipose tissue-derived stromal cells contribute to vascular remodeling during aging.

Xiao‐Xi Pan,Qiang Zhao,Hai‐Qing Li,An‐Qing Chen,Qi‐Hong Wu,Cheng‐Chao Ruan,Yu Ma,Xiu‐Ying Liu,Yan‐Jun Sun,Xiu‐Jie Wang,Ling‐Ran Kong,Ding‐Liang Zhu,Fang Wu,Ping‐Jin Gao,Ji‐Guang Wang

doi:10.1111/acel.12969

Abstract

Aging is an independent risk factor for vascular diseases. Perivascular adipose tissue (PVAT), an active component of the vasculature, contributes to vascular dysfunction during aging. Identification of underlying cell types and their changes during aging may provide meaningful insights regarding the clinical relevance of aging‐related vascular diseases. Here, we take advantage of single‐cell RNA sequence to characterize the resident stromal cells in the PVAT (PVASCs) and identified different clusters between young and aged PVASCs. Bioinformatics analysis revealed decreased endothelial and brown adipogenic differentiation capacities of PVASCs during aging, which contributed to neointimal hyperplasia after perivascular delivery to ligated carotid arteries. Mechanistically, in vitro and in vivo studies both suggested that aging‐induced loss of peroxisome proliferator‐activated receptor‐γ coactivator‐1 α (PGC1α) was a key regulator of decreased brown adipogenic differentiation in senescent PVASCs. We further demonstrated the existence of human PVASCs (hPVASCs) and overexpression of PGC1α improved hPVASC delivery‐induced vascular remodeling. Our finding emphasizes that differentiation capacities of PVASCs alter during aging and loss of PGC1α in aged PVASCs contributes to vascular remodeling via decreased brown adipogenic differentiation.

Highlights

Aging of the population is one of the major challenges facing public health systems
Aging is an independent risk factor for vascular diseases and is associated with functional, structural, and mechanical changes in ar‐ teries independent of disease.(Lakatta & Levy, 2003; Meyer et al, 2016) Previous studies have showed that aging exacerbates neoin‐ tima lesions after vascular injury through promoting macrophage infiltration and higher sensitivity of smooth muscle cell (SMC) to proliferation stimuli. (Eghbalieh et al, 2012; Rodriguez‐Menocal et al, 2014) Aging in‐ duces superoxide production in the Perivascular adipose tissue (PVAT) and contributes to arte‐ rial stiffness
Functional tests showed that there is no significant difference in the migration, pro‐ liferation, and ROS production between young and aged PVAT‐derived stro‐ mal cells (PVASCs)

Summary

| INTRODUCTION

2014; Gomez‐Serrano et al, 2017; Xu et al, 2018) In addition to adipo‐ cytes, PVAT contains macrophages, leukocytes, as well as stromal cells and autonomic nerves.(Brown et al, 2014; Ruan et al, 2015) little is known about the effects of aging on the other cells in the PVAT and their roles in aging‐related vascular diseases. GO analysis further indicated the altered differentiation potential of aging PVASCs, in which muscle cell differentiation, adipocyte differentia‐ tion, and EC differentiation were closely linked to vascular remodeling (Figure 2c, d) Among these putative cell‐type populations, two major clusters of genes are significantly related to adipogenic and endothe‐ lial differentiation. PGC1α‐ overexpression attenuated perivascular collagen deposition, al‐ though it did not significantly affect neointimal hyperplasia in nude mice after ligation injury (Figure 6j, k) These provide direct evidence that the hPVASCs may be involved in the vascular remodeling pro‐ cess via spontaneously differentiating into vascular cells and peri‐ vascular brown adipocytes during aging

| DISCUSSION

| EXPERIMENTAL PROCEDURES

Findings

CONFLICT OF INTEREST