Remodeling of vascular smooth muscle ion channels involved in purinergic signaling in essential hypertension

Zusammenfassung

Essential hypertension is a symptomless, multifactorial genetic disorder, in which inheritance of abnormal genes predisposes the individual to high blood pressure, especially if environmental influences are present. The raise in the arterial blood pressure of hypertensive patients is a result of an imbalance between cardiac output (CO) and total peripheral resistances (TPR). The molecular, functional and structural changes that lead to the chronic TPR increase are not fully understood and several hypotheses have been suggested. Vascular ion channels play crucial roles in the control of vascular tone and contractility by setting the membrane potential of vascular smooth muscle cells (VSMCs). Therefore, the altered expression and function of these VSM channels may contribute to vascular dysfunction and to the pathogenesis of hypertension. Over several years, our group has been exploring the contribution of different VSM ion channels to the molecular mechanisms involved in the physiopathology of essential hypertension. Using a genetic, phenotype-driven mouse model of essential hypertension (BPH and their BPN control mice), the functional expression of different families of K+ channels and voltage-operated Ca2+ channels (VOCCs), and their contribution to the hypertensive phenotype have been widely explored. However, the contribution of other many families of receptors and ion channels, such as the purinergic family of G protein coupled receptors (GPCR) and receptor-operated (ROCs) and Ca2+ activated Cl- (CaCCs) channels are still unknown. This Thesis aims to explore the role of TRPC and ANO1 channels and the P2Y purinergic signaling in the genesis of the hypertensive phenotype in the BPN/BPH model. We have analyzed the mRNA and the protein expression profile of these VSM channels and receptors in mesenteric arteries from BPN and BPH mice. We have also characterized their functional activity using electrophysiology and pressure myography approaches. Our results lead us to the conclusion that GPCR signaling pathways in BPN/PBH mice are mediated by the integrated coupling between GPCRs and TRPC3/6 (Álvarez-Miguel et al., 2016) and ANO1 channels, although the relative importance of those channels seems to be receptor dependent. Although both, TRPC and ANO1 channels contribute to set the resting Vm of VSMCs, ANO1 channels are the essential mediators of the UTP-induced depolarizations. In this context, differences in the functional expression and/or the coupling between GPCRs and TRPC and CaCCs channels working downstream the signaling pathway could contribute to the increased reactivity of BPH arteries, pointing out to all these proteins as new potential therapeutic targets for the treatment of essential hypertension.