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They function as essential molecular regulators of cardiovascular physiology, governing processes from the initiation of cardiac rhythm in the sinoatrial node to the regulation of vascular tone. Their widespread expression in cardiac and vascular tissues, combined with their ability to integrate diverse extracellular signals, positions GPCRs as key regulators of heart rate, contractility, vascular tone, inflammation, and metabolic homeostasis. Recent advances in GPCR structural biology, coupled with mechanistic insights into G\u2010protein\u2010 and \u03b2\u2010arrestin\u2010mediated signaling mechanisms, underscore their central role in both cardiovascular health and disease. Notably, dysregulation of GPCR signaling has emerged as a unifying mechanism across major cardiovascular diseases (CVDs), contributing to pathological remodeling, impaired contractile function, and maladaptive vascular responses. This review uniquely integrates GPCR structural biology, signaling dynamics, and mechanosensitive and biased signaling mechanisms within the cardiovascular system. We discuss the contributions of class A, class B, and other GPCR families to cardiovascular physiology and pathology emphasizing their relevance to the development of targeted interventions for hypertension, heart failure, arrhythmias, atherosclerosis, and related CVDs. Together, these insights establish a contemporary framework for advancing precision GPCR\u2010directed therapies in CVDs. By framing these developments within a mechanistic and translational context, the review offers a timely and clinically significant resource for both basic researchers and clinicians.<\/jats:p>","DOI":"10.1002\/med.70087","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:15:39Z","timestamp":1786968939000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unraveling the Intricacies of G\u2010Protein\u2010Coupled Receptor Signaling in Cardiovascular Diseases: Novel Perspectives From Regulation to Therapeutic Targeting"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2807-1885","authenticated-orcid":false,"given":"Shaherin","family":"Basith","sequence":"first","affiliation":[{"name":"Department of Physiology Ajou University School of Medicine Suwon Republic of Korea"},{"name":"Department of Integrative Biotechnology, College of Biotechnology and Bioengineering Sungkyunkwan University Suwon Gyeonggi\u2010do Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1299-9478","authenticated-orcid":false,"given":"Gwang","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Physiology Ajou University School of Medicine Suwon Republic of Korea"},{"name":"Department of Molecular Science &amp; Technology Ajou University Suwon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"issue":"1","key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/s41392-024-01803-6","article-title":"G Protein\u2010Coupled Receptors (GPCRs): Advances in Structures, Mechanisms, and Drug Discovery","volume":"9","author":"Zhang M.","year":"2024","journal-title":"Signal Transduction and Targeted Therapy"},{"issue":"5","key":"e_1_2_11_3_1","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.tips.2021.10.011","article-title":"Wandering Beyond Small Molecules: Peptides as Allosteric Protein Modulators","volume":"43","author":"Mannes M.","year":"2022","journal-title":"Trends in Pharmacological Sciences"},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","first-page":"128","DOI":"10.3389\/fphar.2018.00128","article-title":"Exploring G Protein\u2010Coupled Receptors (GPCRs) Ligand Space via Cheminformatics Approaches: Impact on Rational Drug Design","volume":"9","author":"Basith S.","year":"2018","journal-title":"Frontiers in Pharmacology"},{"issue":"1","key":"e_1_2_11_5_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1021\/acs.jmedchem.6b01453","article-title":"Recent Advances in Structure\u2010Based Drug Design Targeting Class A G Protein\u2010Coupled Receptors Utilizing Crystal Structures and Computational Simulations","volume":"61","author":"Lee Y.","year":"2018","journal-title":"Journal of Medicinal Chemistry"},{"issue":"7","key":"e_1_2_11_6_1","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1016\/j.cell.2019.04.044","article-title":"Illuminating G\u2010Protein\u2010Coupling Selectivity of GPCRs","volume":"177","author":"Inoue A.","year":"2019","journal-title":"Cell"},{"issue":"3","key":"e_1_2_11_7_1","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/aps.2011.170","article-title":"Structure and Mechanism for Recognition of Peptide Hormones by Class B G\u2010Protein\u2010Coupled Receptors","volume":"33","author":"Pal K.","year":"2012","journal-title":"Acta Pharmacologica Sinica"},{"issue":"12","key":"e_1_2_11_8_1","doi-asserted-by":"crossref","first-page":"2947","DOI":"10.1111\/j.1742-4658.2005.04728.x","article-title":"Allosteric Functioning of Dimeric Class C G\u2010Protein\u2010Coupled Receptors","volume":"272","author":"Pin J. 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