Resumen de Caveolin-1 in cardiovascular pathophysiology: insights into tissue remodeling and cell type-specific functions Marta
Cardiovascular disease (CVD), including atherosclerosis and myocardial infarction, account for a high burden of morbidity and mortality worldwide, and thus constitute a critical research area. Caveolin-1 (CAV1) protein has emerged as a key player in cellular functions associated with pathological processes underlying CVD, such as the transduction of flow patterns and extracellular matrix (ECM) remodeling.
This study focuses on understanding the roles of CAV1 and its phosphorylation at tyrosine 14 (Y14) in regulating the underlying mechanisms of atherosclerosis and cardiac responses to damage, with a special emphasis on tissue remodeling. Additionally, the specific functions of CAV1 in different cell types have been addressed. Different murine models of CVD and in vitro studies have been employed to achieve these objectives.
We showed that endothelial cell-specific deletion of Cav1 exacerbates hypercholesterolemia without increasing lesion extension, whereas vascular smooth muscle cell (VSMC)-specific deletion of Cav1 has no effect on these processes. The absence of CAV1 phosphorylation at Y14 provided modest protection against the development of atherosclerotic plaques at atheroprone sites (APS) but resulted in pathological remodeling of lesions. We demonstrated that aortic VSMCs lacking CAV1 or its Y14 phosphorylation led to an altered ECM composition in vitro, and that in vivo differential remodeling of collagen within the vascular wall occurs in APS through mechanisms dependent on CAV1 expression and its phosphorylation at Y14.
Single-cell RNA sequencing analysis revealed a specific distribution of cellular subpopulations in aortic regions with different atherosclerosis susceptibilities, offering insights into the potential involvement of these populations in atherogenesis.
The regenerative potential of the heart was studied in murine models lacking either CAV1 or its phosphorylation at Y14 using cryoinjury in neonatal mice as a model of cardiac damage. We observed that these models present basal hypertrophy in the heart at both cellular and tissue level at neonatal stages, which progresses into pathological remodeling following cardiac injury. Although lesion extension was not affected in knockout and mutant mice at the studied time points, they exhibited reduced cardiac proliferative capacity, deficient macrophage recruitment, and impaired collagen remodelling within cardiac lesions. Finally, the cell-autonomous role of CAV1 in myeloid cells was ruled out as the responsible mechanism for the reduced immune cell infiltration observed in hearts lacking CAV1.
This comprehensive study aimed to shed light on the specific roles of CAV1 in CVD, contributing to the understanding of cardiovascular pathophysiology and potentially identifying therapeutic targets for these diseases
