Enhanced vasorin signaling mitigates adverse cardiovascular remodeling

Arterial stiffening is a critical risk factor contributing to the exponential rise in age-associated cardiovascular disease incidence. This process involves age-induced arterial proinflammation, collagen deposition, and calcification, which collectively contribute to arterial stiffening. The primary driver of proinflammatory processes leading to collagen deposition in the arterial wall is the transforming growth factor-beta1 (TGF-beta 1) signaling. Activation of this signaling is pivotal in driving vascular extracellular remodeling, eventually leading to arterial fibrosis and calcification. Interestingly, the glycosylated protein vasorin (VASN) physically interacts with TGF-beta 1, and functionally restraining its proinflammatory fibrotic signaling in arterial walls and vascular smooth muscle cells (VSMCs). Notably, as age advances, matrix metalloproteinase type II (MMP-2) is activated, which effectively cleaves VASN protein in both arterial walls and VSMCs. This age-associated/MMP-2-mediated decrease in VASN levels exacerbates TGF-beta 1 activation, amplifying arterial fibrosis and calcification in the arterial wall. Importantly, TGF-beta 1 is a downstream molecule of the angiotensin II (Ang II) signaling pathway in the arterial wall and VSMCs, which is modulated by VASN. Indeed, chronic administration of Ang II to young rats significantly activates MMP-2 and diminishes the VASN expression to levels comparable to untreated older control rats. This review highlights and discusses the role played by VASN in mitigating fibrosis and calcification by alleviating TGF-beta 1 activation and signaling in arterial walls and VSMCs. Understanding these molecular physical and functional interactions may pave the way for establishing VASN-based therapeutic strategies to counteract adverse age-associated cardiovascular remodeling, eventually reducing the risk of cardiovascular diseases.Vasorin (VASN)-mediated arterial proinflammatory signaling pathway: (1) inhibits transforming growth factor-beta1 (TGF-beta 1) fibrotic signaling pathway; (2) negatively affects angiotensin II (Ang II)-TGF-beta 1 fibrotic and inflammatory activated MMP pathway; (3) exerts antiaging effects via the blockade of Ang II and matrix metalloproteinase type II activation pathway; and (4) miR146a modulates VASN expression and effects. VANS signaling potentially mitigate adverse cardiovascular remodeling and retards cardiovascular disease.image