PGF2α-FP Receptor Ameliorates Senescence of VSMCs in Vascular Remodeling by Src/PAI-1 Signal Pathway
Bo-Ang Hu1, Wen-Wen Sai1,2, Jun Yuan1,3
1The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
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.
Insights
The FP receptor promotes vascular aging by inducing smooth muscle cell senescence and oxidative stress. Inhibiting this pathway ameliorates vascular aging and fibrosis.
Area of Science:
- Cardiovascular Research
- Cellular Aging
- Vascular Biology
Background:
- Vascular smooth muscle cell (VSMC) senescence contributes to vascular remodeling in aging.
- Prostaglandin F2α (PGF2α) via its FP receptor is implicated in cardiovascular diseases (CVDs), hypertension, and cardiac fibrosis.
- The specific role of the FP receptor in senescence-induced arteriosclerosis requires further investigation.
Purpose of the Study:
- To investigate the role of the FP receptor in VSMC senescence and vascular aging.
- To elucidate the molecular mechanisms by which the FP receptor influences vascular aging.
- To determine if targeting the FP receptor can ameliorate senescence-related vascular dysfunction.
Main Methods:
- Analysis of FP receptor expression in aged mouse aortas and senescent VSMCs.
- Gene silencing of the FP receptor in VSMCs.
- Assessment of oxidative stress markers, PAI-1, MMPs, and extracellular matrix (ECM) deposition.
- Evaluation of senescence markers (P16, P21, P53, GLB1) and the Src/PAI-1 signaling pathway.
Main Results:
- FP receptor expression was elevated in aged mouse aortas and senescent VSMCs.
- FP receptor gene silencing improved vascular aging, reduced oxidative stress, decreased PAI-1 and MMPs, and lessened ECM deposition.
- Inhibition of the FP receptor/Src/PAI-1 pathway reduced VSMC aging in vitro, indicated by decreased senescence markers.
- The FP receptor promotes VSMC senescence via the Src/PAI-1 signaling pathway.
Conclusions:
- The FP receptor acts as a promoter of vascular aging.
- It induces cellular aging, oxidative stress, and vascular remodeling through the upregulation of Src and PAI-1.
- Targeting the FP receptor/Src/PAI-1 pathway offers a potential therapeutic strategy for vascular aging and related diseases.
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