Molecular and Cellular Underpinnings of Primary Hypertension: An Integrative Mechanistic Framework

Abstract

Hypertension is a highly prevalent clinical condition and a major contributor to global cardiovascular morbidity and mortality. Despite extensive research, its complex and multifaceted pathogenesis is yet to be fully elucidated. This paper explores the updated understanding of primary hypertension as a systemic disorder rather than an isolated vascular or renal abnormality. At the center of this multifactorial disease lie three primary and interrelated pathophysiological mechanisms: dysregulation of the renin–angiotensin–aldosterone system, dysfunction of the central nervous system, and activation of inflammatory and oxidative stress pathways. These core drivers not only interact with each other in a self-reinforcing cycle but also serve as convergence points for a range of additional contributors. Specifically, suboptimal dietary patterns, salt sensitivity, gut microbiota dysbiosis, circadian rhythm disruption, and insulin resistance act by modulating these central processes, thereby perpetuating blood pressure elevation. This review further elaborates on how these mechanisms span across multiple organ systems, driving vascular, renal, neurohumoral, and immune dysfunction. Taken together, this perspective underscores the need for integrated, upstream-targeted therapeutic strategies. By highlighting the interconnected nature of these drivers and contributors, this paper provides a comprehensive framework to inform future research and guide more effective preventive and management approaches for hypertension.