Mas-Related G Protein-Coupled Receptor Member D Sustains Hypertension

Abstract

Hypertension and its associated complications, including vascular remodeling, pose a major burden on global public health. However, the role of Mas-related G protein-coupled receptor member D (MrgD) in hypertension remains incompletely understood. In this study, we observed upregulated MrgD expression in the arterial tissues of hypertensive patients and animal models. In Sprague-Dawley rats, MrgD overexpression elevated blood pressure (BP) and promoted mesenteric vascular remodeling, whereas MrgD knockdown in spontaneously hypertensive rats normalized BP and ameliorated vascular remodeling. Consistently, MrgD knockout mice exhibited resistance to angiotensin II (Ang II)-induced hypertension and vascular injury. Mechanistic investigations demonstrated that MrgD facilitated vascular remodeling in vascular smooth muscle cells (VSMCs) through the voltage-gated L-type Ca²⁺ channel (Cav1.2)-Ca²⁺/calmodulin-dependent protein kinase IIγ (CaMKIIγ) signaling axis. Co-immunoprecipitation coupled with mass spectrometry and in vitro functional assays confirmed that Ang II enhanced the interaction among MrgD, CaMKIIγ, and Cav1.2, thereby promoting VSMC phenotypic switch. Through artificial intelligence-driven screening combined with functional validation, we identified risperidone as a small-molecule inhibitor of MrgD that effectively attenuated hypertension and vascular remodeling. These findings established MrgD as a key contributor to the pathogenesis of hypertension and underscore its potential as a promising therapeutic target for hypertension and its associated vascular complications.

Keywords

artery remodeling / Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) / hypertension / Mas-related G protein-coupled receptor member D (MrgD) / voltage-gated L-type Ca²⁺ channel (Cav1.2)

References

[1] U. Derhaschnig, C. Testori, E. Riedmueller, S. Aschauer, M. Wolzt, and B. Jilma, “Hypertensive Emergencies Are Associated With Elevated Markers of Inflammation, Coagulation, Platelet Activation and Fibrinolysis,” Journal of Human Hypertension 27 (2013): 368–373.

[2] B. Zhou, P. Perel, G. A. Mensah, and M. Ezzati, “Global Epidemiology, Health Burden and Effective Interventions for Elevated Blood Pressure and Hypertension,” Nature Reviews Cardiology 18 (2021): 785–802.

[3] J. D. Humphrey, “Mechanisms of Vascular Remodeling in Hypertension,” American Journal of Hypertension 34 (2021): 432–441.

[4] L. Te Riet, J. H. van Esch, A. J. Roks, A. H. van den Meiracker, and A. H. Danser, “Hypertension: Renin-Angiotensin-Aldosterone System Alterations,” Circulation Research 116 (2015): 960–975.

[5] J. Ma, Y. Li, X. Yang, et al., “Signaling Pathways in Vascular Function and Hypertension: Molecular Mechanisms and Therapeutic Interventions,” Signal Transduction and Targeted Therapy 8 (2023): 168.

[6] S. Heeneman, J. C. Sluimer, and M. J. Daemen, “Angiotensin-Converting Enzyme and Vascular Remodeling,” Circulation Research 101 (2007): 441–454.

[7] N. M. Santiago, P. S. Guimarães, R. A. Sirvente, et al., “Lifetime Overproduction of Circulating Angiotensin-(1-7) Attenuates Deoxycorticosterone Acetate-Salt Hypertension-Induced Cardiac Dysfunction and Remodeling,” Hypertension 55 (2010): 889–896.

[8] Y. Shi, C. S. Lo, R. Padda, et al., “Angiotensin-(1-7) Prevents Systemic Hypertension, Attenuates Oxidative Stress and Tubulointerstitial Fibrosis, and Normalizes Renal Angiotensin-Converting Enzyme 2 and Mas Receptor Expression in Diabetic Mice,” Clinical Science 128 (2015): 649–663.

[9] V. B. Patel, S. Bodiga, R. Basu, et al., “Loss of Angiotensin-Converting Enzyme-2 Exacerbates Diabetic Cardiovascular Complications and Leads to Systolic and Vascular Dysfunction: A Critical Role of the Angiotensin II/AT1 Receptor Axis,” Circulation Research 110 (2012): 1322–1335.

[10] R. Q. Lautner, D. C. Villela, R. A. Fraga-Silva, et al., “Discovery and Characterization of Alamandine: A Novel Component of the Renin-Angiotensin System,” Circulation Research 112 (2013): 1104–1111.

[11] C. Yang, X. Wu, Y. Shen, C. Liu, X. Kong, and P. Li, “Alamandine Attenuates Angiotensin II-Induced Vascular Fibrosis via Inhibiting p38 MAPK Pathway,” European Journal of Pharmacology 883 (2020): 173384.

[12] N. Shi, X. Mei, and S. Y. Chen, “Smooth Muscle Cells in Vascular Remodeling,” Arteriosclerosis, Thrombosis, and Vascular Biology 39 (2019): e247–e252.

[13] S. Moosmang, V. Schulla, A. Welling, et al., “Dominant Role of Smooth Muscle L-Type Calcium Channel Cav1.2 for Blood Pressure Regulation,” EMBO Journal 22 (2003): 6027–6034.

[14] D. W. Wilde, P. B. Furspan, and J. F. Szocik, “Calcium Current in Smooth Muscle Cells From Normotensive and Genetically Hypertensive Rats,” Hypertension 24 (1994): 739–746.

[15] R. H. Cox and I. M. Lozinskaya, “Augmented Calcium Currents in Mesenteric Artery Branches of the Spontaneously Hypertensive Rat,” Hypertension 26 (1995): 1060–1064.

[16] Y. Ohya, T. Tsuchihashi, S. Kagiyama, I. Abe, and M. Fujishima, “Single L-Type Calcium Channels in Smooth Muscle Cells From Resistance Arteries of Spontaneously Hypertensive Rats,” Hypertension 31 (1998): 1125–1129.

[17] A. Pesic, J. A. Madden, M. Pesic, and N. J. Rusch, “High Blood Pressure Upregulates Arterial L-Type Ca²⁺ Channels: Is Membrane Depolarization the Signal?,” Circulation Research 94 (2004): e97–e104.

[18] M. T. Johnson, A. Gudlur, X. Zhang, et al., “L-Type Ca²⁺ Channel Blockers Promote Vascular Remodeling Through Activation of STIM Proteins,” Proceedings of the National Academy of Sciences of the United States of America 117 (2020): 17369–17380.

[19] A. Hudmon and H. Schulman, “Neuronal CA²⁺/Calmodulin-Dependent Protein Kinase II: The Role of Structure and Autoregulation in Cellular Function,” Annual Review of Biochemistry 71 (2002): 473–510.

[20] A. M. Prasad, D. W. Nuno, O. M. Koval, et al., “Differential Control of Calcium Homeostasis and Vascular Reactivity by Ca²⁺/Calmodulin-Dependent Kinase II,” Hypertension 62 (2013): 434–441.

[21] M. M. Muthalif, N. A. Karzoun, I. F. Benter, et al., “Functional Significance of Activation of Calcium/Calmodulin-Dependent Protein Kinase II in Angiotensin II-Induced Vascular Hyperplasia and Hypertension,” Hypertension 39 (2002): 704–709.

[22] Y. Li, B. Li, W. D. Chen, and Y. D. Wang, “Role of G-Protein Coupled Receptors in Cardiovascular Diseases,” Frontiers in Cardiovascular Medicine 10 (2023): 1130312.

[23] K. Zhao, D. Hua, C. Yang, et al., “Nuclear Import of Mas-Related G Protein-Coupled Receptor Member D Induces Pathological Cardiac Remodeling,” Cell Communication and Signaling 21 (2023): 181.

[24] S. Nishimura, M. Uno, Y. Kaneta, et al., “MRGD, a MAS-Related G-Protein Coupled Receptor, Promotes Tumorigenesis and Is Highly Expressed in Lung Cancer,” PLoS One 7 (2012): e38618.

[25] J. Hami, V. von Bohlen Und Halbach, A. Tetzner, T. Walther, and O. von Bohlen Und Halbach, “Localization and Expression of the Mas-Related G-Protein Coupled Receptor Member D (MrgD) in the Mouse Brain,” Heliyon 7 (2021): e08440.

[26] Y. Suzuki, T. Ozawa, T. Kurata, et al., “A Molecular Complex of Cav1.2/CaMKK2/CaMK1a in Caveolae Is Responsible for Vascular Remodeling via Excitation-Transcription Coupling,” Proceedings of the National Academy of Sciences of the United States of America 119 (2022): e2117435119.

[27] F. E. Hengel, C. Sommer, and U. Wenzel, “[Arterial Hypertension],” Deutsche Medizinische Wochenschrift 147 (2022): 414–428.

[28] J. Yu, S. Wang, W. Shi, et al., “Roxadustat Prevents Ang II Hypertension by Targeting Angiotensin Receptors and eNOS,” JCI Insight 6, no. 18 (2021): e133690.

[29] A. H. Danser, J. P. van Kats, P. J. Admiraal, et al., “Cardiac Renin and Angiotensins. Uptake From Plasma Versus In Situ Synthesis,” Hypertension 24 (1994): 37–48.

[30] R. Choudhary, M. S. Kapoor, A. Singh, and S. H. Bodakhe, “Therapeutic Targets of Renin-Angiotensin System in Ocular Disorders,” Journal of Current Ophthalmology 29 (2017): 7–16.

[31] I. C. G. Jesus, T. Mesquita, R. A. Souza Santos, and S. Guatimosim, “An Overview of Alamadine/MrgD Signaling and Its Role in Cardiomyocytes,” American Journal of Physiology-Cell Physiology 324 (2023): C606–C613.

[32] R. A. S. Santos, W. O. Sampaio, A. C. Alzamora, et al., “The ACE2/Angiotensin-(1-7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1-7),” Physiological Reviews 98 (2018): 505–553.

[33] F. P. de Souza-Neto, M. Carvalho Santuchi, E. S. M. de Morais, M. J. Campagnole-Santos, and R. F. da Silva, “Angiotensin-(1-7) and Alamandine on Experimental Models of Hypertension and Atherosclerosis,” Current Hypertension Reports 20 (2018): 17.

[34] B. Habiyakare, H. Alsaadon, M. L. Mathai, A. Hayes, and A. Zulli, “Reduction of Angiotensin A and Alamandine Vasoactivity in the Rabbit Model of Atherogenesis: Differential Effects of Alamandine and Ang(1-7),” International Journal of Experimental Pathology 95 (2014): 290–295.

[35] A. Korneva and J. D. Humphrey, “Maladaptive Aortic Remodeling in Hypertension Associates With Dysfunctional Smooth Muscle Contractility,” American Journal of Physiology Heart and Circulatory Physiology 316 (2019): H265–H278.

[36] M. A. Song, C. Dasgupta, and L. Zhang, “Chronic Losartan Treatment Up-Regulates AT1R and Increases the Heart Vulnerability to Acute Onset of Ischemia and Reperfusion Injury in Male Rats,” PLoS One 10 (2015): e0132712.

[37] C. J. Zhang, Y. N. Shi, D. F. Liao, K. Du, and L. Qin, “[Molecular Mechanism of Vascular Remodeling in Hypertension and Chinese Medicine Intervention],” Sheng Li Xue Bao [Acta Physiologica Sinica] 71 (2019): 235–247.

[38] M. Nieves-Cintrón, G. C. Amberg, M. F. Navedo, J. D. Molkentin, and L. F. Santana, “The Control of Ca²⁺ Influx and NFATc3 Signaling in Arterial Smooth Muscle During Hypertension,” Proceedings of the National Academy of Sciences of the United States of America 105 (2008): 15623–15628.

[39] D. Ghosh, A. U. Syed, M. P. Prada, et al., “Calcium Channels in Vascular Smooth Muscle,” Advances in Pharmacology 78 (2017): 49–87.

[40] X. Q. Hu and L. Zhang, “Oxidative Regulation of Vascular Ca(v)1.2 Channels Triggers Vascular Dysfunction in Hypertension-Related Disorders,” Antioxidants (Basel) 11, no. 12 (2022): 2432.

[41] E. Cingolani, G. A. Ramirez Correa, E. Kizana, M. Murata, H. C. Cho, and E. Marbán, “Gene Therapy to Inhibit the Calcium Channel Beta Subunit: Physiological Consequences and Pathophysiological Effects in Models of Cardiac Hypertrophy,” Circulation Research 101 (2007): 166–175.

[42] M. J. Berridge, P. Lipp, and M. D. Bootman, “The Versatility and Universality of Calcium Signalling,” Nature Reviews Molecular Cell Biology 1 (2000): 11–21.

[43] M. Mederos y Schnitzler, U. Storch, S. Meibers, et al., “Gq-Coupled Receptors as Mechanosensors Mediating Myogenic Vasoconstriction,” EMBO Journal 27 (2008): 3092–3103.

[44] L. Ji, H. Zhu, H. Chen, et al., “Modulation of CaV1.2 Calcium Channel by Neuropeptide W Regulates Vascular Myogenic Tone via G Protein-Coupled Receptor 7,” Journal of Hypertension 33 (2015): 2431–2442.

[45] S. Weiss, S. Oz, A. Benmocha, and N. Dascal, “Regulation of Cardiac L-Type Ca²⁺ Channel CaV1.2 via the β-Adrenergic-cAMP-Protein Kinase A Pathway: Old Dogmas, Advances, and New Uncertainties,” Circulation Research 113 (2013): 617–631.

[46] T. Shinohara, M. Harada, K. Ogi, et al., “Identification of a G Protein-Coupled Receptor Specifically Responsive to Beta-Alanine,” Journal of Biological Chemistry 279 (2004): 23559–23564.

[47] O. A. Bachkoenig, B. Gottschalk, R. Malli, and W. F. Graier, “An Unexpected Effect of Risperidone Reveals A Nonlinear Relationship Between Cytosolic Ca²⁺ and Mitochondrial Ca²⁺ Uptake,” Current Topics in Membranes 90 (2022): 13–35.

[48] S. Altinkiliç, M. Naziroğlu, A. C. Uğuz, and R. Ozcankaya, “Fish Oil and Antipsychotic Drug Risperidone Modulate Oxidative Stress in PC12 Cell Membranes Through Regulation of Cytosolic Calcium Ion Release and Antioxidant System,” Journal of Membrane Biology 235 (2010): 211–218.

[49] S. N. Wu, C. R. Jan, H. F. Li, and H. T. Chiang, “Characterization of Inhibition by Risperidone of the Inwardly Rectifying K(+) Current in Pituitary GH(3) Cells,” Neuropsychopharmacology 23 (2000): 676–689.

[50] S. Li, Y. Nong, Q. Gao, et al., “Astragalus Granule Prevents Ca²⁺ Current Remodeling in Heart Failure by the Downregulation of CaMKII,” Evidence-Based Complementary and Alternative Medicine 2017 (2017): 7517358.

[51] J. Heineke and J. D. Molkentin, “Regulation of Cardiac Hypertrophy by Intracellular Signalling Pathways,” Nature Reviews Molecular Cell Biology 7 (2006): 589–600.

[52] O. E. Reyes Gaido, L. J. Nkashama, K. L. Schole, et al., “CaMKII as a Therapeutic Target in Cardiovascular Disease,” Annual Review of Pharmacology and Toxicology 63 (2023): 249–272.

[53] J. Beckendorf, M. M. G. van den Hoogenhof, and J. Backs, “Physiological and Unappreciated Roles of CaMKII in the Heart,” Basic Research in Cardiology 113 (2018): 29.

[54] F. Z. Saddouk, R. Ginnan, and H. A. Singer, “Ca(2+)/Calmodulin-Dependent Protein Kinase II in Vascular Smooth Muscle,” Advances in Pharmacology 78 (2017): 171–202.

[55] H. Li, W. Li, A. K. Gupta, P. J. Mohler, M. E. Anderson, and I. M. Grumbach, “Calmodulin Kinase II Is Required for Angiotensin II-Mediated Vascular Smooth Muscle Hypertrophy,” American Journal of Physiology Heart and Circulatory Physiology 298 (2010): H688–H698.

[56] S. J. House, R. G. Ginnan, S. E. Armstrong, and H. A. Singer, “Calcium/Calmodulin-Dependent Protein Kinase II-Delta Isoform Regulation of Vascular Smooth Muscle Cell Proliferation,” American Journal of Physiology-Cell Physiology 292 (2007): C2276–C2287.

[57] M. Z. Mercure, R. Ginnan, and H. A. Singer, “CaM Kinase II Delta2-Dependent Regulation of Vascular Smooth Muscle Cell Polarization and Migration,” American Journal of Physiology-Cell Physiology 294 (2008): C1465–C1475.

[58] S. J. House and H. A. Singer, “CaMKII-Delta Isoform Regulation of Neointima Formation After Vascular Injury,” Arteriosclerosis, Thrombosis, and Vascular Biology 28 (2008): 441–447.

[59] F. Z. Saddouk, L. Y. Sun, Y. F. Liu, et al., “Ca²⁺/Calmodulin-Dependent Protein Kinase II-γ (CaMKIIγ) Negatively Regulates Vascular Smooth Muscle Cell Proliferation and Vascular Remodeling,” FASEB Journal 30 (2016): 1051–1064.

[60] S. Hinuma, Y. Habata, R. Fujii, et al., “A Prolactin-Releasing Peptide in the Brain,” Nature 393 (1998): 272–276.

[61] A. M. Prasad, D. A. Morgan, D. W. Nuno, et al., “Calcium/Calmodulin-Dependent Kinase II Inhibition in Smooth Muscle Reduces Angiotensin II-Induced Hypertension by Controlling Aortic Remodeling and Baroreceptor Function,” Journal of the American Heart Association 4 (2015): e001949.

[62] A. M. Prasad, P. Ketsawatsomkron, D. W. Nuno, et al., “Role of CaMKII in Ang-II-Dependent Small Artery Remodeling,” Vascular Pharmacology 87 (2016): 172–179.

[63] M. Stojkovic, B. Radmanovic, M. Jovanovic, V. Janjic, N. Muric, and D. I. Ristic, “Risperidone Induced Hyperprolactinemia: From Basic to Clinical Studies,” Frontiers in Psychiatry 13 (2022): 874705.

[64] J. K. Rybakowski, “Application of Antipsychotic Drugs in Mood Disorders,” Brain Sciences 13, no. 3 (2023): 414.

[65] S. Y. Xie, S. Q. Liu, T. Zhang, et al., “USP28 Serves as a Key Suppressor of Mitochondrial Morphofunctional Defects and Cardiac Dysfunction in the Diabetic Heart,” Circulation 149 (2024): 684–706.

[66] H. Lv, C. Wang, Z. Liu, et al., “Suppression of the Prostaglandin I2-Type 1 Interferon Axis Induces Extramedullary Hematopoiesis to Promote Cardiac Repair After Myocardial Infarction,” Circulation 151 (2025): 1730–1747.

[67] Y. Zheng, Y. Cao, W. Wang, et al., “Dusp14-Mediated Dephosphorylation of MLKL Protects Against Cardiomyocyte Necroptosis in Hypothyroidism-Induced Heart Failure,” Circulation 151 (2025): 1797–1813.

[68] J. Shi, C. Yang, J. Zhang, et al., “NAT10 Is Involved in Cardiac Remodeling Through ac4C-Mediated Transcriptomic Regulation,” Circulation Research 133 (2023): 989–1002.

[69] E. Gerdts, I. Sudano, S. Brouwers, et al., “Sex Differences in Arterial Hypertension,” European Heart Journal 43 (2022): 4777–4788.

[70] P. Li, B. Liu, X. Wu, et al., “Perirenal Adipose Afferent Nerves Sustain Pathological High Blood Pressure in Rats,” Nature Communications 13 (2022): 3130.

[71] O. Trott and A. J. Olson, “AutoDock Vina: Improving the Speed and Accuracy of Docking With a New Scoring Function, Efficient Optimization, and Multithreading,” Journal of Computational Chemistry 31 (2010): 455–461.

[72] J. A. Castro-Mondragon, R. Riudavets-Puig, I. Rauluseviciute, et al., “JASPAR 2022: The 9th Release of the Open-Access Database of Transcription Factor Binding Profiles,” Nucleic Acids Research 50 (2022): D165–D173.

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