Sex-specific modulation of T-type voltage-gated calcium channels in the renal artery of hypertensive rats

TL;DR

The study finds that hypertension affects male and female rats differently in terms of calcium channel activity and nitric oxide signaling in the renal artery.

Contribution

The paper reveals sex-specific modulation of T-type calcium channels and NO signaling in hypertension, suggesting targeted therapies for females.

Findings

Male hypertensive rats show increased mRNA of T-type VGCCs and eNOS without functional changes.

Female hypertensive rats exhibit enhanced T-type VGCC activity and reduced NO release.

Female rats show compensatory downregulation of T-type VGCC mRNA despite increased activity.

Abstract

Hypertension contributes to cardiovascular disease, with growing evidence of sex-specific differences in its underlying mechanisms. T-type voltage-gated calcium channels (VGCCs) have emerged as key regulators of vascular tone, particularly under conditions of nitric oxide (NO) deficiency. However, their role in mediating vascular dysfunction across sexes remains poorly understood.

This study examined the role of T-type VGCCs and their modulation by NO in the renal artery of male and female spontaneously hypertensive rats (SHR). Vascular reactivity was assessed through phenylephrine-induced contractions in the presence or absence of nickel chloride (NiCl2), a T-type VGCC blocker, and L-NAME, an inhibitor of nitric oxide synthase (NOS). Gene expression of T-type VGCCs (CaV3.1 and CaV3.2) and eNOS was quantified by RT-PCR. Oxidative stress parameters in leukocytes were assessed by flow cytometry to explore the systemic redox.

Hypertension induced a rightward shift of the acetylcholine-mediated vasorelaxation curve. In male rats, hypertension did not significantly alter the phenylephrine concentration-response curve. A single data point showed a significant difference following incubation with L-NAME. The contribution of T-type VGCCs to vascular reactivity remained unchanged. Male SHRs displayed increased mRNA expression of CaV3.1, CaV3.2, and eNOS, yet showed no corresponding increase in T-type VGCC activity or NO availability. Conversely, in female SHR, phenylephrine concentration-response curve showed a leftward shift, reduced NO release, and increased participation of T-type VGCCs in response to phenylephrine. Furthermore, pharmacological inhibition of NO synthesis in female WKY rats, used to simulate hypertensive conditions, enhanced the involvement of T-type VGCCs in phenylephrine-induced vasoconstriction. mRNA expression of eNOS was not modified by hypertension in females. Despite the heightened T-type VGCCs activity, female SHRs had reduced mRNA expression of CaV3.1 and CaV3.2, suggesting a potential compensatory downregulation. Finally, leukocytes of male SHR exhibited significantly increased production of H2O2 and ONOO− compared to the other studied groups, suggesting that hypertension contributes to a greater oxidative stress in male.

These findings reveal sex-specific differences in the role of T-type VGCCs during hypertension and underscore the therapeutic potential of targeting T-type VGCCs, particularly in females, as a sex-specific strategy for more effective and personalized hypertension management.

Sex-specific vascular modulation of T-type voltage-gated calcium channels (VGCCs) and nitric oxide (NO) signalling in renal artery of Spontaneously Hypertensive Rats (SHR). Hypertension leads to distinct molecular and functional changes in male and female rat renal arteries. Male rats with hypertension exhibit elevated T-type VGCCs and eNOS mRNA expression (Nos3) without corresponding functional changes in T-type VGCCs activity or NO release in response to phenylephrine (PHE). Female rats with hypertension display enhanced T-type VGCCs functional activity and reduced NO release in response to PHE, with downregulation of T-type VGCCs mRNA. These findings reveal striking sex-specific differences, underscoring the therapeutic potential of targeting T-type VGCCs for personalized hypertension management, particularly in females.Two illustrated rats are shown under male and female symbols, with a central box titled “Sex-specific vascular modulation in the renal artery of SHR.” Below, 4 comparison results: 1- T-type VGCCs vascular contribution to PHE; 2- NO release in response to PHE; 3- mRNA expression of T-type VGCCs and 4- mRNA expression of NOS3. For males 1 and 2 are “no affect” and 3 and 4 with upward arrows. For females 1 is with upward arrow, 2 and 3 downward arrows and for 4 “no affect”.

Sex-specific vascular modulation of T-type voltage-gated calcium channels (VGCCs) and nitric oxide (NO) signalling in renal artery of Spontaneously Hypertensive Rats (SHR). Hypertension leads to distinct molecular and functional changes in male and female rat renal arteries. Male rats with hypertension exhibit elevated T-type VGCCs and eNOS mRNA expression (Nos3) without corresponding functional changes in T-type VGCCs activity or NO release in response to phenylephrine (PHE). Female rats with hypertension display enhanced T-type VGCCs functional activity and reduced NO release in response to PHE, with downregulation of T-type VGCCs mRNA. These findings reveal striking sex-specific differences, underscoring the therapeutic potential of targeting T-type VGCCs for personalized hypertension management, particularly in females.

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