The Role of Brain Cellular Senescence in the Sexual Dimorphism of Hypertension.

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PROJECT SUMMARY It is estimated that about 10 million deaths worldwide each year are associated with hypertension, but unfortunately, the etiology is unknown in 95% of cases. Furthermore, the risk of hypertension is greater in men than pre-menopausal women. However, post-menopause, the female risk of hypertension exceeds that of age- matched males, pointing to the hormone estrogen as protective against hypertension. In contrast to the cardiovascular protective effects of estrogen, the hormone angiotensin II (Ang II) is well-recognized as a driver of hypertension. Ang II acts within the brain to elevate sympathetic nervous system outflow, which subsequently leads to increases in blood pressure. Indeed, hypertensive patients display elevated levels of Ang II and sympathetic overactivity. As a peptide hormone, Ang II is too large to cross the blood-brain-barrier and influences cardiovascular regulation at specialized circumventricular nuclei that lack a blood-brain-barrier, particularly the subfornical organ (SFO). Ang II-induced cellular stressors including oxidative stress and endoplasmic reticulum dysfunction within the SFO are strongly implicated in Ang II-induced hypertension. However, the integrative downstream cellular mechanisms by which these alterations in the SFO lead to chronic changes in neuronal function remains unclear. Interestingly, these stressors have been shown to induce cellular senescence - a complex cellular phenotype characterized by marked changes in cell metabolism, macromolecular damage, and a secretory pro-inflammatory environment known as the senescence associated secretory phenotype (SASP). Our key preliminary data in murine models reveals that central nervous system senescence contributes to hypertension. Additional exciting evidence indicates that Ang II drives senescence and SASP activation in the SFO of males, but not in females. Building upon this, the current proposal will test the hypothesis that estrogen is protective against SFO cellular senescence/SASP and subsequently hypertension development. To address this hypothesis, we will comprehensively characterize SFO cellular senescence/SASP in male versus female mice during Ang II-induced hypertension development using molecular, histological, and innovative in vivo imaging techniques. We will further determine the functional consequence of cellular senescence on SFO neurons and how the sexual dimorphism of hypertension is driven by the interplay between SFO Ang II-mediated senescence and estrogen. Findings from this proposal have the potential to advance our understanding of sexually dimorphic brain mechanisms in hypertension pathology, which may spur novel therapeutic treatments for hypertension in both sexes.