TY - JOUR

T1 - Acute, pro-contractile effects of prorenin on rat mesenteric arteries

AU - Rognant, Salomé

AU - Baldwin, Samuel N.

AU - Pritchard, Harry A.T.

AU - Greenstein, Adam

AU - Calloe, Kirstine

AU - Aalkjaer, Christian

AU - Jepps, Thomas A.

N1 - Publisher Copyright: © 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

PY - 2023

Y1 - 2023

N2 - Prorenin and the prorenin receptor ((P)RR) are important, yet controversial, members of the renin–angiotensin–aldosterone system. The ((P)RR) is expressed throughout the body, including the vasculature, however, the direct effect of prorenin on arterial contractility is yet to be determined. Within rat mesenteric arteries, immunostaining and proximity ligation assays were used to determine the interacting partners of (P)RR in freshly isolated vascular smooth muscle cells (VSMCs). Wire myography examined the functional effect of prorenin. Simultaneous changes in [Ca2+]i and force were recorded in arteries loaded with Fura-2AM. Spontaneously transient outward currents were recorded via perforated whole-cell patch-clamp configuration in freshly isolated VSMCs. We found that the (P)RR is located within a distance of less than 40 nm from the V-ATPase, caveolin-1, ryanodine receptors, and large conductance Ca2+-activated K+ channels (BKCa) in VSMCs. [Ca2+]i imaging and isometric tension recordings indicate that 1 nM prorenin enhanced α1-adrenoreceptor-mediated contraction, associated with an increased number of Ca2+ waves, independent of voltage-gated Ca2+ channels activation. Incubation of VSMCs with 1 nM prorenin decreased the amplitude and frequency of spontaneously transient outward currents and attenuated BKCa-mediated relaxation. Inhibition of the V-ATPase with 100 nM bafilomycin prevented prorenin-mediated inhibition of BKCa-derived relaxation. Renin (1 nM) had no effect on BKCa-mediated relaxation. In conclusion, prorenin enhances arterial contractility by inhibition of BKCa and increasing intracellular Ca2+ release. It is likely that this effect is mediated through a local shift in pH upon activation of the (P)RR and stimulation of the V-ATPase.

AB - Prorenin and the prorenin receptor ((P)RR) are important, yet controversial, members of the renin–angiotensin–aldosterone system. The ((P)RR) is expressed throughout the body, including the vasculature, however, the direct effect of prorenin on arterial contractility is yet to be determined. Within rat mesenteric arteries, immunostaining and proximity ligation assays were used to determine the interacting partners of (P)RR in freshly isolated vascular smooth muscle cells (VSMCs). Wire myography examined the functional effect of prorenin. Simultaneous changes in [Ca2+]i and force were recorded in arteries loaded with Fura-2AM. Spontaneously transient outward currents were recorded via perforated whole-cell patch-clamp configuration in freshly isolated VSMCs. We found that the (P)RR is located within a distance of less than 40 nm from the V-ATPase, caveolin-1, ryanodine receptors, and large conductance Ca2+-activated K+ channels (BKCa) in VSMCs. [Ca2+]i imaging and isometric tension recordings indicate that 1 nM prorenin enhanced α1-adrenoreceptor-mediated contraction, associated with an increased number of Ca2+ waves, independent of voltage-gated Ca2+ channels activation. Incubation of VSMCs with 1 nM prorenin decreased the amplitude and frequency of spontaneously transient outward currents and attenuated BKCa-mediated relaxation. Inhibition of the V-ATPase with 100 nM bafilomycin prevented prorenin-mediated inhibition of BKCa-derived relaxation. Renin (1 nM) had no effect on BKCa-mediated relaxation. In conclusion, prorenin enhances arterial contractility by inhibition of BKCa and increasing intracellular Ca2+ release. It is likely that this effect is mediated through a local shift in pH upon activation of the (P)RR and stimulation of the V-ATPase.

KW - calcium waves

KW - large-conductance calcium-activated potassium channels

KW - pH

KW - prorenin

KW - V-ATPase

KW - vasculature

U2 - 10.1096/fj.202301480

DO - 10.1096/fj.202301480

M3 - Journal article

C2 - 37994700

AN - SCOPUS:85177673631

VL - 37

JO - F A S E B Journal

JF - F A S E B Journal

SN - 0892-6638

IS - 12

M1 - e23282

ER -