Angiotensin and neuroimmune activation in hypertension

University Of Florida, Gainesville FL

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Hypertension (HTN) is the single most prevalent risk factor for cardiovascular disease, diabetes, obesity, and metabolic syndrome. Despite advances in lifestyle modification and multi-drug based therapies, 20-30% of all hypertensive patients remain resistant with uncontrolled high blood pressure. These patients exhibit autonomic dysregulation due to elevated sympathetic activity and norepinephrine (NE) spillover, and low parasympathetic activity, indicating that their HTN is of neurogenic origin. Thus, we believe that a mechanism-based breakthrough is imperative to develop novel strategies to prevent and perhaps even cure neurogenic hypertension. Our evidence of a dysfunctional neural-bone marrow (BM) communication in neurogenic hypertension represents this breakthrough. Based on our published and preliminary data and evidence from the literature, we propose the following hypothesis: hypertensive signals such as increased angiotensin II are recognized by the hypothalamic paraventricular nucleus (PVN), resulting in activation of resident microglia, an increase in activity of pre-autonomic neurons, and enhancement of sympathetic drive to the BM. This autonomic imbalance to the BM leads to an increase in inflammatory cells that mobilize to the brain, differentiate into activated microglia, and perpetuate the hypertensive state. Four specific aims are proposed to support/refute the brain-BM axis hypothesis and provide conceptual support for its translation into a formal clinical trial: Aim 1 investigates the hypothesis that Ang II-induced increases in microglial activation in the PVN, mediated by the CCL2/CCR2 chemokine system, are key early events in enhancing SNA in HTN. Aim 2 investigates the hypothesis that sympathetic nerve activity to the BM is increased in Ang II-induced HTN. Aim 3 evaluates the hypothesis that extravasation of BM inflammatory progenitor cells to the PVN contributes to overall increase in activated microglia in HTN. Aim 4 investigates the hypothesis that minocycline treatment would produce antihypertensive effects in drug-resistant hypertensive patients by decreasing cerebral microglia activity. These studies will utilize state-of-the-art integrative physiological genomic techniques including chronic brain and bone marrow cell/tissue specific gene modification, imaging in animals and humans, electrophysiological recordings of sympathetic fibers to the BM and pre-autonomic neurons, to support our novel hypothesis. Thus, outcomes of this investigation will be valuable for paradigm changing approaches for the treatment of resistant neurogenic hypertension.