Alpha1A- and Beta3-Adrenoceptors Interplay in Adipose Multipotent Mesenchymal Stromal Cells: A Novel Mechanism of Obesity-Driven Hypertension

Abstract

Hypertension is a major risk factor for cardiovascular diseases, such as strokes and myocardial infarctions. Nearly 70% of hypertension onsets in adults can be attributed to obesity, primarily due to sympathetic overdrive and the dysregulated renin-angiotensin system. Sympathetic overdrive increases vasoconstriction via α1-adrenoceptor activation on vascular cells. Despite the fact that a sympathetic outflow increases in individuals with obesity, as a rule, there is a cohort of patients with obesity who do not develop hypertension. In this study, we investigated how adrenoceptors’ expression and functioning in adipose tissue are affected by obesity-driven hypertension. Here, we demonstrated that α1A is a predominant isoform of α1-adrenoceptors expressed in the adipose tissue of patients with obesity, specifically by multipotent mesenchymal stromal cells (MSCs). These cells respond to prolonged exposure to noradrenaline in the model of sympathetic overdrive through the elevation of α1A-adrenoceptor expression and signaling. The extent of MSCs’ response to noradrenaline correlates with a patient’s arterial hypertension. scRNAseq analysis revealed that in the model of sympathetic overdrive, the subpopulation of MSCs with contractile phenotype expanded significantly. Elevated α1A-adrenoceptor expression is triggered specifically by beta3-adrenoceptors. These data define a novel pathophysiological mechanism of obesity-driven hypertension by which noradrenaline targets MSCs to increase microvessel constrictor responsivity.

Noradrenaline and serotonin-dependent sensitization of MSCs to noradrenaline

“…Since the noradrenaline solution is added to the MSCs directly during time-lapse recording, the researcher does not have the opportunity to mix the combined solutions. In cells capable of sensitization in response to preincubation with noradrenaline or 5-HT, the sensitivity of cells to noradrenaline increases [6] , and the number of cells responding with calcium to noradrenaline increases [1 , 2] . The second parameter is more convenient for recording in ordinary experiments.…”

“…In cells capable of sensitization in response to preincubation with noradrenaline or 5-HT, the sensitivity of cells to noradrenaline increases [6] , and the number of cells responding with calcium to noradrenaline increases [1 , 2] . The second parameter is more convenient for recording in ordinary experiments.…”

“…We showed that both noradrenaline and 5-HT, but not histamine, adenosine or dopamine increases the sensitivity of MSCs to noradrenaline [2] . Using this protocol, we showed that noradrenaline specifically acts through β3-adrenoceptors [1] , whereas the 5-HT effect is mediated by HTR6 [2] . Stimulation of these receptors in MSCs up-regulates the expression of ɑ1a-adrenoceptors [5] and increases MSCs sensitivity to noradrenaline up to 5 times [6] .…”

“…In contrast, neither hormone was not able to elevate sensitivity to noradrenaline in MSCs isolated from obese normotensive donors. The level of observed increase in the noradrenaline responsiveness was well correlated with mean blood pressure and systolic blood pressure of obese patients, but not diastolic blood pressure [1 , 2] .…”

“… Value of the Protocol: This protocol was used to discover novel hormonal cross-talks (circuits) in adipose tissue-derived MSCs [4] , [5] , [6] . Increase of MSCs sensitivity to noradrenaline by other cAMP-mobilizing hormones is a prognostic marker for the development of obesity-driven arterial hypertension [1 , 2] . …”