The Roles of Aldosterone and Protein Kinase a Signaling in Vascular Smooth Muscle Cell Calcification

Abstract

Vascular calcification is a disease prevalent in the elderly population. Intimal calcification, the dominant form, is calcification of the inner layer of the blood vessel wall and arises primarily after atherosclerotic plaque accumulation, thereby following the vascular distribution patterns of atherosclerosis. Medial calcification, calcium phosphate deposition in the middle layer of blood vessels, is much less common and is correlated with different disease states, such as type II diabetes and chronic kidney disease. It is widely recognized that vascular smooth muscle cells of the medial layer play a major role in the pathogenesis of vascular calcification. This study focuses on how aldosterone and cAMP/PKA signaling affect the calcification of vascular smooth muscle cells. We investigated two independent pathways by which aldosterone may induce calcification. First, we discovered that aldosterone is a promoter of fibrosis, a potential mediator of vascular calcification, by inducing the expression of connective tissue growth factor. Second, we showed potential effects of aldosterone on phosphate/pyrophosphate imbalance, known to be an important determinant of calcification. In addition, aldosterone modulates expression of miRNAs predicted to regulate both pathways. Finally, PKA signaling has been previously shown to induce calcification of vascular smooth muscle cells by regulating phosphate/pyrophosphate metabolism. Here, we show that PKA signaling does, indeed, disrupt phosphate/pyrophosphate regulation; however, it appears to induce an anti-calcific response, directly contradicting the results of prior studies. In summary, aldosterone induces vascular medial calcification through fibrosis and phosphate/pyrophosphate imbalance, which is potentially regulated by miRNAs, and PKA signaling contributes to phosphate/pyrophosphate regulation in a protective manner against calcification.