Microvascular angiotensin II type 2 receptor function is enhanced in young females and declines in a model of murine aging

Abstract

Introduction: Angiotensin II (AngII) affects cardiovascular health, mediating impacts through AngII type 1 (AT1R) and type 2 (AT2R) receptors. The present study investigated sex and aging-related differences in microvascular AngII receptor function in mice and humans. Methods: Mesenteric resistance arteries (MRA) were isolated from 3-, 12-, and 18-month-old female and male C57/Bl6 mice. Wire myography was used to measure vasoconstriction to AngII and vasodilation to an AT2R agonist (compound 21, C21). Seven healthy adults (3 premenopausal women and 4 age-matched men) were recruited to participate in a study measuring cutaneous microvascular vasoconstriction to AngII in the presence and absence of 10 μM PD123319, an AT2R antagonist. Results: In murine MRA, AngII-induced constriction increases by 18 months in females and by 12 months in males. AT2R-mediated vasodilation was reduced with age in females only, which corresponds with a female-specific decrease in mesenteric AT2R mRNA expression. AT2R inhibition enhances AngII-induced constriction in young female, but not male, mice. Clinical data support that premenopausal women have attenuated AngII constriction vs. men, which is abrogated by AT2R inhibition. AT2R expression is greater in primary aortic smooth muscle cells, but not endothelial cells, from young women compared with men. Conclusions: These data demonstrate enhanced microvascular AT2R function in young female mice and young women. There is a female-specific loss of AT2R function with age in mice, concomitant with declining AT2R expression. These findings implicate AT2R as a sex-specific target for microvascular dysfunction and aging-associated cardiovascular disease.

Keywords

Microvascular function / aging / angiotensin II type 2 receptor / sex differences / skin blood flow / cutaneous

References

[1] Tsao CW,Almarzooq ZI.Heart disease and stroke statistics-2023 update: a report from the american heart association.Circulation2023;147:e93-621

[2] DeFilippis EM.Is it time for sex-specific guidelines for cardiovascular disease?.J Am Coll Cardiol2021;78:189-92

[3] Paz Ocaranza M,García L.Counter-regulatory renin-angiotensin system in cardiovascular disease.Nat Rev Cardiol2020;17:116-29 PMCID:PMC7097090

[4] Miller AJ.The renin-angiotensin system and cardiovascular autonomic control in aging.Peptides2022;150:170733 PMCID:PMC8923940

[5] Wang M,Lakatta EG.Central arterial aging and angiotensin II signaling.Curr Hypertens Rev2010;6:266-81 PMCID:PMC3058527

[6] DuPont JJ,Kenney RM.Sex differences in the time course and mechanisms of vascular and cardiac aging in mice: role of the smooth muscle cell mineralocorticoid receptor.Am J Physiol Heart Circ Physiol2021;320:H169-80 PMCID:PMC7847078

[7] Berry C,Dominiczak AF,Johns DG.Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide.Am J Physiol Heart Circ Physiol2001;281:H2337-65

[8] Peluso AA,Andersen K.Identification of protein phosphatase involvement in the AT₂ receptor-induced activation of endothelial nitric oxide synthase.Clin Sci2018;132:777-90

[9] Steckelings UM,Sturrock ED.The angiotensin AT₂ receptor: from a binding site to a novel therapeutic target.Pharmacol Rev2022;74:1051-135 PMCID:PMC9553111

[10] You D,Baron C,Widdop RE.High blood pressure reduction reverses angiotensin II type 2 receptor-mediated vasoconstriction into vasodilation in spontaneously hypertensive rats.Circulation2005;111:1006-11 PMCID:PMC2234478

[11] Sampson AK,Jones ES,Widdop RE.Enhanced angiotensin II type 2 receptor mechanisms mediate decreases in arterial pressure attributable to chronic low-dose angiotensin II in female rats.Hypertension2008;52:666-71

[12] Touyz RM,He G,Schiffrin EL.Role of AT₂ receptors in angiotensin II-stimulated contraction of small mesenteric arteries in young SHR.Hypertension1999;33:366-72

[13] Viswanathan M,Correa FM.Changes in expression of angiotensin receptor subtypes in the rat aorta during development.Biochem Biophys Res Commun1991;179:1361-7

[14] Chatziantoniou C.Angiotensin receptor sites in renal vasculature of rats developing genetic hypertension.Am J Physiol1993;265:F853-62

[15] Savoia C,Volpe M.Angiotensin type 2 receptor in resistance arteries of type 2 diabetic hypertensive patients.Hypertension2007;49:341-6

[16] Lang JA.Age-related differences in the cutaneous vascular response to exogenous angiotensin II.Am J Physiol Heart Circ Physiol2019;316:H516-21

[17] Schwartz KS,Stanhewicz AE.Angiotensin II type 2 receptor-mediated dilation is greater in the cutaneous microvasculature of premenopausal women compared with men.J Appl Physiol2023;135:1236-42

[18] Herrick AL,Overbeck K.A phase 2 trial investigating the effects of the angiotensin II type 2 receptor agonist C21 in systemic sclerosis-related Raynaud’s.Rheumatology2023;62:824-8 PMCID:PMC9891408

[19] Tornling G,Porter JC.Seven days treatment with the angiotensin II type 2 receptor agonist C21 in hospitalized COVID-19 patients; a placebo-controlled randomised multi-centre double-blind phase 2 trial.EClinicalMedicine2021;41:101152 PMCID:PMC8542174

[20] Xue B,Hay M.Sex differences in the development of angiotensin II-induced hypertension in conscious mice.Am J Physiol Heart Circ Physiol2005;288:H2177-84

[21] Xue B,Lubahn DB.Estrogen receptor-alpha mediates estrogen protection from angiotensin II-induced hypertension in conscious female mice.Am J Physiol Heart Circ Physiol2007;292:H1770-6

[22] Tatchum-Talom R,Martin DS.Sexual dimorphism in angiotensin II-induced hypertension and vascular alterations.Can J Physiol Pharmacol2005;83:413-22

[23] Widdop RE,Henrion D.Vascular angiotensin AT2 receptors in hypertension and ageing.Clin Exp Pharmacol Physiol2008;35:386-90

[24] Koike G,Yamada T,Jacob HJ.Human type 2 angiotensin II receptor gene: cloned, mapped to the X chromosome, and its mRNA is expressed in the human lung.Biochem Biophys Res Commun1994;203:1842-50

[25] Mishra JS,Kumar S.Testosterone downregulates angiotensin II type-2 receptor via androgen receptor-mediated ERK1/2 MAP kinase pathway in rat aorta.J Renin Angiotensin Aldosterone Syst2016;17:147032031667487 PMCID:PMC5465964

[26] Mishra JS,Qi QR.Estrogen receptor-β mediates estradiol-induced pregnancy-specific uterine artery endothelial cell angiotensin type-2 receptor expression.Hypertension2019;74:967-74 PMCID:PMC6739159

[27] Nelson JF,Randall PK,Finch CE.A longitudinal study of estrous cyclicity in aging C57BL/6J mice: I. Cycle frequency, length and vaginal cytology.Biol Reprod1982;27:327-39

[28] Kim SK,DuPont JJ.Smooth muscle cell-mineralocorticoid receptor as a mediator of cardiovascular stiffness with aging.Hypertension2018;71:609-21 PMCID:PMC5843545

[29] DuPont JJ,Davel AP.Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with aging.JCI Insight2016;1:e88942 PMCID:PMC5033871

[30] DuPont JJ,Farquhar WB,Edwards DG.NADPH oxidase-derived reactive oxygen species contribute to impaired cutaneous microvascular function in chronic kidney disease.Am J Physiol Renal Physiol2014;306:F1499-506 PMCID:PMC4059972

[31] Dupont JJ,Townsend RR.Ascorbic acid or L-arginine improves cutaneous microvascular function in chronic kidney disease.J Appl Physiol2011;111:1561-7 PMCID:PMC3233898

[32] Turner CG,Nielsen KE,Feresin RG.Effects of biological sex and oral contraceptive pill use on cutaneous microvascular endothelial function and nitric oxide-dependent vasodilation in humans.J Appl Physiol2023;134:858-67 PMCID:PMC10042598

[33] Turner CG,Grosch C,Otis JS.Endothelin a receptor inhibition increases nitric oxide-dependent vasodilation independent of superoxide in non-hispanic black young adults.J Appl Physiol2023;134:891-9 PMCID:PMC10042601

[34] Reckelhoff JF.Mechanisms of sex and gender differences in hypertension.J Hum Hypertens2023;37:596-601

[35] Mishra JS.Activation of angiotensin type 2 receptor attenuates testosterone-induced hypertension and uterine vascular resistance in pregnant rats.Biol Reprod2021;105:192-203 PMCID:PMC8660162

[36] Widdop RE,Hannan RE.Angiotensin AT2 receptors: cardiovascular hope or hype?.Br J Pharmacol2003;140:809-24 PMCID:PMC1574085

[37] González-Blázquez R,Fernández-Alfonso MS.C21 preserves endothelial function in the thoracic aorta from DIO mice: role for AT2, Mas and B2 receptors.Clin Sci2021;135:1145-63

[38] Pinaud F,Dumont O.Paradoxical role of angiotensin II type 2 receptors in resistance arteries of old rats.Hypertension2007;50:96-102 PMCID:PMC2231526

[39] Waheed N,Malas W.Sex differences in non-obstructive coronary artery disease.Cardiovasc Res2020;116:829-40

[40] Toering TJ,Visser FW.Gender differences in response to acute and chronic angiotensin II infusion: a translational approach.Physiol Rep2015;3:e12434 PMCID:PMC4552520

[41] Brown RD,Head GA,Widdop RE.Sex differences in the pressor and tubuloglomerular feedback response to angiotensin II.Hypertension2012;59:129-35

[42] Sampson AK,Moritz KM.The arterial depressor response to chronic low-dose angiotensin II infusion in female rats is estrogen dependent.Am J Physiol Regul Integr Comp Physiol2012;302:R159-65

[43] Barsha G,Walton SL.In aged females, the enhanced pressor response to angiotensin II is attenuated by estrogen replacement via an angiotensin type 2 receptor-mediated mechanism.Hypertension2021;78:128-37

[44] Dai SY,Zhang YP,Shen Y.Brain endogenous angiotensin II receptor type 2 (AT2-R) protects against DOCA/salt-induced hypertension in female rats.J Neuroinflammation2015;12:47 PMCID:PMC4355980

[45] Hilliard LM,Kett MM.Gender differences in pressure-natriuresis and renal autoregulation: role of the Angiotensin type 2 receptor.Hypertension2011;57:275-82

[46] Mirabito KM,Kett MM.Sex- and age-related differences in the chronic pressure-natriuresis relationship: role of the angiotensin type 2 receptor.Am J Physiol Renal Physiol2014;307:F901-7

[47] Manrique-Acevedo C,Padilla J,Gozal D.Obesity and cardiovascular disease in women.Int J Obes2020;44:1210-26 PMCID:PMC7478041

[48] Lum-Naihe K,Mahmood A.Cardiovascular disease progression in female zucker diabetic fatty rats occurs via unique mechanisms compared to males.Sci Rep2017;7:17823 PMCID:PMC5736602

[49] Belenchia AM,DeMarco VG.Cardiovascular protective effects of NP-6A4, a drug with the FDA designation for pediatric cardiomyopathy, in female rats with obesity and pre-diabetes.Cells2023;12:1373 PMCID:PMC10216951

[50] Gavini MP,Belenchia AM.Suppression of inflammatory cardiac cytokine network in rats with untreated obesity and pre-diabetes by AT2 receptor agonist NP-6A4.Front Pharmacol2021;12:693167 PMCID:PMC8253363

[51] Baiardi G,Armando I,Tyurmin D.Estrogen upregulates renal angiotensin II AT1 and AT2 receptors in the rat.Regul Pept2005;124:7-17

[52] Macova M,Zhou J.Estrogen reduces aldosterone, upregulates adrenal angiotensin II AT2 receptors and normalizes adrenomedullary Fra-2 in ovariectomized rats.Neuroendocrinology2008;88:276-86 PMCID:PMC2677380

[53] Stewart JM,Raghunath N,Medow MS.Intradermal angiotensin II administration attenuates the local cutaneous vasodilator heating response.Am J Physiol Heart Circ Physiol2008;295:H327-34 PMCID:PMC2494761

[54] Barsha G,Mirabito Colafella KM.Sex- and age-related differences in arterial pressure and albuminuria in mice.Biol Sex Differ2016;7:57 PMCID:PMC5109725

[55] McCurley A,Bender SB.Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors.Nat Med2012;18:1429-33 PMCID:PMC3491085