Neutrophils play a pivotal role in vascular aging

Project Summary/Abstract Socioeconomic status and psychological stressors are known to contribute significantly to vascular aging, a process of gradual deterioration of blood vessel structure and function, leading to the development of cardiovascular diseases (CVD). Chronic inflammation is believed to mediate vascular aging. We discovered that mice lacking neutrophil elastase (NE), a serine protease released by neutrophils, significantly reverse aging-related arterial stiffness, a hallmark of vascular aging. Our observations suggest that neutrophils and NE are pivotal in aging-related vascular stiffening. Our parent grant, funded by NHLBI, investigates the molecular mechanism by which NE interacts with the vascular cells, contributing to inflammation, fibrosis, and calcification in the arterials. However, whether stress-related vascular aging is mediated by neutrophil activation and subsequent vascular inflammatory damage is unknown. We hypothesize that social stress can activate the sympathetic nerve system (SNS) and release catecholamines from the sympathetic nerve terminus. Catecholamines stimulate the cAMP signaling and activate the hormone-sensitive lipase (HSL) pathway, leading to lipolysis and free fatty acid (FFA) formation. FFAs increase G-CSF expression, stimulating neutrophil production and mobilization from BM to blood circulation, increasing neutrophil-vascular cell interaction and inflammatory injury, and accelerating vascular aging and the development of cardiovascular diseases. Our NE knockout (NEKO) mice provide a unique and valuable tool to evaluate the potential link between neutrophil activation and social stress-related acceleration of vascular aging. Here, we propose to examine and compare social isolation-induced stress responses and signaling in bone marrow (BM), neutrophil activation, and vascular stiffening with NEKO mice and wild-type littermates. This supplement proposal integrates well with and within the scope of the parent project, connecting neutrophil activation and vascular aging. Successful completion of the project provides a solid foundation for a new RO1 proposal for the candidate and new insight into the cellular and molecular mechanisms of social stress-related vascular aging and cardiovascular diseases.