Abstract
Senescence in vascular smooth muscle cells (VSMCs) is involved in vascular remodeling of aged mice. ProstaglandinF2α- (PGF2α-) FP receptor plays a critical role in cardiovascular diseases (CVDs), hypertension, and cardiac fibrosis. However, its role in senescence-induced arteriosclerosis is yet to be fully elucidated. In this study, we found that FP receptor expression increased in aged mouse aortas and senescence VSMCs. FP receptor gene silencing can ameliorate vascular aging and inhibit oxidative stress, thereby reducing the expression of PAI-1, inhibiting the activation of MMPs, and ultimately improving the excessive deposition of ECM and delaying the process of vascular fibrosis. FP receptor could promote VSMC senescence by upregulated Src/PAI-1 signal pathway, and inhibited FP receptor/Src/PAI-1 pathway could ameliorate VSMCs aging in vitro, evidenced by the decrease of senescence-related proteins P16, P21, P53, and GLB1 expressions. These results suggested that FP receptor is a promoter of vascular aging, by inducing cellular aging, oxidative stress, and vascular remodeling via Src and PAI-1 upregulation.
Highlights
With the increase of human life expectancy, deferring or preventing the occurrence of aging and aging-related diseases has become one of the urgent problems to be solved
Western blot showed that the relative contents of the age-related markers P16, P21 and P53 in aortic vessels were significantly higher in old mice than in young mice (Supplementary Figure 1a)
When Human aortic smooth muscle cells (HASMCs) were stimulated by high glucose (HG) and PGF2α, the expressions of p-Src and Plasminogen activator inhibitor 1 (PAI-1) increased compared with the NG group (Supplementary Figure 5). These results suggested that HG may induce senescence of primary rat vascular smooth muscle cells (VSMCs) and HASMCs through the PGF2α-FP receptor/Src/PAI-1 signaling pathway
Summary
With the increase of human life expectancy, deferring or preventing the occurrence of aging and aging-related diseases has become one of the urgent problems to be solved. Common pathophysiological mechanisms of aging include oxidative stress, mitochondrial dysfunction, chronic low-grade inflammation, genomics homeostasis imbalance, telomere shortening, cell senescence, and epigenetic changes [1]. Studies have found that senescence of vascular cells, especially vascular smooth muscle cells (VSMCs), plays an important role in Oxidative Medicine and Cellular Longevity the occurrence and development of arteriosclerosis [3]. By secreting a variety of cytokines and growth factors, aging VSMCs can change the local microenvironment of tissues and promote the occurrence of inflammatory response and vascular sclerosis [4], thereby aggravating the development of atherosclerosis and hypertension. Further study on the relationship between cellular signaling pathways and age-related vascular dysfunction may contribute to a better understanding of vascular aging
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