A Role for Brain Cellular Senescence in the Pathogenesis of Hypertension
Open Access DepositedHypertension, or high blood pressure, affects an estimated 33% of adults worldwide. A major challenge for treating hypertensive patients is that the etiology is unclear in many cases, an alarming issue considering that hypertension is a leading risk factor for many life-threatening conditions. Over the past several decades, it has become increasingly clear that the actions of the peptide hormone angiotensin II (Ang-II) in the central nervous system (CNS) are central in driving hypertension development. However, Ang-II is too large to cross the blood-brain-barrier and instead acts at a specialized brain regions known as the circumventricular organs (CVOs). In particular, within the subfornical organ (SFO), a CVO well-recognized for its role in cardiovascular regulation, Ang-II induces cellular stressors known to mediate hypertension development, including oxidative stress, endoplasmic reticulum stress, and inflammation. However, the underlying mechanisms that integrate these stressors to drive hypertension remain incompletely defined. In this dissertation, we hypothesized that cellular senescence in the SFO may be a novel mechanism for Ang-II-induced hypertension development. There is mounting evidence that cellular senescence is a complex, heterogeneous cellular phenotype that is strongly implicated in aging and other disease conditions closely associated with hypertension. Importantly, cellular senescence can be induced by the same pro-hypertensive stressors that occur in the SFO to mediate Ang-II-induced hypertension development. Thus, we first sought to determine if there is a role for senescent cells in Ang-II-induced hypertension development. Our data indicate that global removal of senescent cells prevents Ang-II-induced hypertension development, and induction of CNS-specific cellular senescence results in increases in blood pressure. Building upon our initial findings, we next aimed to characterize cellular senescence specifically in the SFO and found increased gene and protein expression of cellular senescence markers in the SFO of male mice during Ang-II-induced hypertension. The increase in senescence was paralleled by the inflammatory senescence-associated secretory phenotype (SASP). Interestingly, the upregulation of senescence and SASP markers was not observed in the SFO of female mice, a finding that is consistent with literature that females are relatively protected against hypertension development. When examining cellular senescence in a cell-type specific manner, our studies indicate that senescent SFO neurons and astrocytes exhibit differing phenotypes during Ang-II-induced hypertension development. Taken together, these findings suggest that cellular senescence and SASP occurs in the SFO during Ang-II-induced hypertension development in both a cell type- and sex-dependent manner. Ultimately, a central goal for this dissertation was to discern the contribution of SFO cellular senescence in driving hypertension development. Based on previously literature and our current findings, we expected that targeting senescent cells in the SFO would prevent Ang-II-induced hypertension development. We performed selective knockdown of the upstream senescence mediator p19ARF in the SFO using viral targeting in p19ARF-floxed male mice, paired with radiotelemetry recordings. SFO-specific knockdown of p19ARF partially alleviated hypertension development in response to Ang-II, indicating a role for p19ARF-p21CIP1/WAF1-related senescence in hypertension development. Although it is well-known that Ang-II signaling within the SFO is a key mechanism for hypertension development, our results reveal cellular senescence to be a previously unknown stressor that occurs at the SFO during Ang-II-induced hypertension development. Thus, this work holds implications for unraveling the complexity of the pathogenesis of hypertension and the potential to provide new therapeutic targets for antihypertensive therapies.
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