The role of Smooth muscle cell PARP1 in vascular aging
Description: Cardiovascular disease (CVD) is the most common cause of morbidity and mortality worldwide. Aging-associated arterial stiffening is an independent risk factor for CVD in both men and women. Strategies to elucidate the molecular mechanisms driving aging-associated arterial stiffening and to identify novel therapeutic targets to mitigate its progression represent a critical unmet need. Vascular aging is linked to DNA damage and increase of senescence molecules, which affects arterial integrity and correlates with overactivation of poly(ADP-ribose) polymerase 1 (PARP1). PARP1 is an enzyme essential for detecting and repairing DNA damage. A key contributor to arterial stiffening is increased intrinsic vascular smooth muscle cells (SMCs) stiffness, driven by cytoskeletal remodeling that enhances integrin expression and its interaction with fibronectin, ultimately impairing arterial compliance. Limited studies suggest that PARP1 inhibition and regulation reduce vascular fibrosis in hypertensive animal models and alleviate microvascular damage and aortic SMCs loss in aged mice. Based on our preliminary data, we hypothesize that smooth muscle cell PARP1 (SMC-PARP1) contributes to the development of vascular aging and arterial stiffening through promotion of vascular remodeling and intrinsic smooth muscle cell stiffness. To investigate the role of SMC-PARP1 in aging-associated arterial stiffness in males and females, we will complete the following three aims: 1) Determine the role of SMC-PARP1 in aging-associated arterial stiffness, intrinsic smooth muscle cell stiffness and measure markers of DNA damage and cellular senescence in young (3-month-old) and elderly (18-month-old) male and female SMC-PARP1-KO and littermate SMC-PARP1-intact control mice, 2) Determine the role of DNA damage and cellular senescence in SMC-PARP1-mediated arterial aging in human cells, and 3) Test the therapeutic potential of chronic PARP1 inhibition to mitigate aging-associated arterial stiffness in aged male and female mice treated with either vehicle or PJ-34 (PARP1 inhibitor) for 4 weeks. The proposed studies will contribute to the basic understanding of the molecular mechanisms of aging-associated arterial stiffness in males and females. These results also have substantial clinical significance by providing support for novel therapeutic treatments to improve CVD outcomes in women and men, supporting the AHA’s core mission to facilitate longer and healthier lives.
Funder: American Heart Association
Amount: $163,900
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2026-01-01
End date: 2027-12-31
Investigators: Karla Oliveira, Karla Oliveira
Institution: Tufts Medical Center
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 0
Funder award ID: 26POST1564343
OpenAlex ID: G5648697453