Regulation of NO Synthesis by Caveolin-1: A Review of Its Importance in Blood Vessels, Perivascular Adipose Tissue and in Atherosclerosis

Caveolin-1 (Cav-1) is a protein found in various forms and locations within cells and tissues throughout the body. Studying its structure and function provides valuable in-sights into key cellular processes such as growth, death, and cell signalling. Expanding our understanding of Cav-1 and its roles across different organs and disease conditions may reveal its potential as a target for developing novel treatments and therapeutic strategies. Cav-1 is a master regulator of endothelial nitric oxide synthase (eNOS), tonically inhibiting its activity to ensure balanced nitric oxide (NO) production. While this mechanistic relationship is well defined in endothelial cells, its role in the pathobi-ology of atherosclerosis remains complex, particularly within perivascular adipose tissue (PVAT), a layer of fat surrounding blood vessels. PVAT is not merely a structural support; it is a metabolically active tissue capable of producing NO, adipokines, and inflammatory mediators, and it also expresses Cav-1. These characteristics allow PVAT to directly influence vascular function and may contribute to the paradoxical roles of Cav-1 observed in different stages and sites of atherosclerosis. The Problem: Human studies present a challenge: loss of function Cav-1 mutations are linked to pulmonary arterial hypertension (PAH), suggesting a protective vascular role. Conversely, in atherosclerosis, Cav-1 is frequently upregulated in diseased vessels but whether this reflects increased expression, altered function, or both remains un-clear. In addition, does this upregulation reflect a compensatory mechanism to regu-late uncoupled eNOS, or a pathological process that aggravates disease progression by further reducing bioactive NO availability? The vast majority of studies establishing the Cav-1/eNOS interaction (where Cav-1 tonically inhibits eNOS, preventing its hyperactivation) have been conducted in endo-thelial cells from mice, rats, or cultured cell lines. The direct extrapolation of this mechanism to perivascular adipose tissue (PVAT), a distinct tissue with adipocytes, immune cells, and stromal cells, is not fully validated except in a few studies.