Reduced Age-Related Increase in Blood Pressure via Modulation of Vasoconstriction

The research linked here is an excellent example of the way in which most initiatives in medicine focus on compensatory adjustments to the disease state rather than on addressing root causes. The authors of this paper produce a beneficial reduction in age-related increase in blood pressure by altering the operation of vasoconstriction, an approach which does nothing at all to address the stiffening of blood vessel tissues that causes the high blood pressure of hypertension, and is therefore somewhat limited in the scope of improvements that it can produce. Even mild hypertension is so very damaging to health in old age that any approaches to safely reducing blood pressure should be celebrated, but nonetheless a research community that adopts a strategy of ignoring root causes is a research community that will continue to produce marginal therapies that can only modestly delay the inevitable results of aging. Only by repairing the root cause damage that results in age-related changes like arterial stiffening and hypertension can the length of healthy life be greatly extended, and age-related disease ended entirely.

Advancing age is a universal, potent, and currently un-modifiable risk factor for the development of hypertension and cardiovascular disease. Essential hypertension (high blood pressure (BP) without a secondary cause) is nearly an absolute consequence of aging in developed nations, affecting 60% of Americans over the age of 60 and 80% of the rapidly growing population over 80. Hypertension (HTN) is a substantial source of morbidity and mortality in the elderly, as high BP increases the risk of heart attack, stroke, vascular dementia, heart failure, kidney failure, and death. Despite this, only half of hypertensives over 50 years of age are controlled with current therapies.

The kidney is an established target of many antihypertensive therapies because it is a critical regulator of BP by modulating sodium and water balance. Perhaps less appreciated is the concept that in response to increases in blood volume from renal mechanisms and vasoconstrictor pathways that are enhanced with aging, smooth muscle cells (SMC) in the resistance vasculature constrict, thereby increasing peripheral vascular resistance and exacerbating hypertension. Thus, the vasculature is also an important contributor to the development of hypertension and to BP control. In humans and rodents, vascular aging is associated with enhanced vascular oxidative stress and increased responsiveness to the vasoconstrictor hormone angiotensin II (AngII) and these factors contribute to enhanced vasoconstriction with aging. However, the molecular mechanisms driving these vascular changes that contribute to hypertension with aging have not been elucidated.

Although the adrenal hormone aldosterone and its mineralocorticoid receptor (MR) are well known regulators of BP by promoting renal sodium reabsorption in the kidney, we previously demonstrated that MR is also expressed and functional in human vascular SMC. Moreover, we found that mice with MR specifically deleted from SMC in adulthood (SMC-MR-KO mice), are protected from the modest aging-associated rise in systolic BP that occurs in MR-intact mice, despite no change in renal function, sodium handling, or serum aldosterone levels. Rather, aged SMC-MR-KO mice had decreased vasoconstriction in response to increased intravascular pressure (termed myogenic tone) and were protected from AngII-induced vasoconstriction and vascular oxidative stress, important drivers of vascular dysfunction and hypertension with aging. Thus, the SMC-MR-KO mouse was used to explore mechanisms driving vasoconstriction with aging as these mechanisms may contribute to hypertension in elderly humans and could suggest new therapeutic strategies to improve BP control. We discovered that with aging, MR expression rises in resistance vessels along with a decline in microRNA (miR)-155 and increased expression of predicted miR-155 targets including the L-type calcium channel (LTCC) subunit Cav1.2 and the angiotensin type-1 receptor (AgtR1), genes that contribute to vasoconstriction and oxidative stress in aging mice. Restoration of miR-155 in aged vessels decreased target gene expression and vasoconstriction. Finally, in older humans, changes in miR-155 levels in response to MR antagonism correlated with improved BP response to therapy.

Overall, these data provide new insight into mechanisms driving vasoconstriction with aging that may contribute to the associated rise in BP. The data are consistent with the model in which enhanced SMC-MR expression and activity in aging resistance vessels suppresses vascular miR-155 transcription resulting in increased LTCC and AgtR1 expression. In this way, SMC-MR contributes to maintenance of myogenic tone and LTCC-induced constriction and primes the vasculature for enhanced AngII-induced oxidative stress and vasoconstriction, important components of the vascular aging phenotype that contributes to hypertension with aging. These results support the need for further studies in humans to determine if miR-155 could be a biomarker of MR activation in the setting of vascular aging with important implications for improving BP control in the rapidly aging population.



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