PGF2α-FP Receptor Ameliorates Senescence of VSMCs in Vascular Remodeling by Src/PAI-1 Signal Pathway

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.

The Link between Prostanoids and Cardiovascular Diseases

“…In contrast, the deletion of the FP receptor determines blood pressure reduction and a slower development of the same pathology, as reported in [ 129 ]. FP receptor activity seems to increase the aging of VSMCs and their dysfunction, which is delayed by FP receptor deletion [ 130 ]. Overall, it is possible to state that PGF2α/FP axis plays a critical role in cardiovascular dysfunction, being involved in the development of atherosclerosis, hypertension, and cardiovascular fibrosis.…”

Prostanoids in Cardiac and Vascular Remodeling

“…218 vascular fibrosis, and oxidative stress by preventing the upregulation of the Src/PAI-1 signal pathway. 219 FPr deletion reduces BP after Ang II or PGF 2α infusion and retards atherosclerosis through the impairment of the renin-angiotensin-aldosterone system. 220 Moreover, FPr dimerizes with the Ang II type 1 receptor in VSMCs, contributing to the regulation of BP.…”

“…218 FPr silencing improves age-related hypertension, vascular fibrosis, and oxidative stress by preventing the upregulation of the Src/PAI-1 signal pathway. 219…”