PDF(Pubmed)
Abstract：
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-β1) 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-β1, 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-β1 activation, amplifying arterial fibrosis and calcification in the arterial wall. Importantly, TGF-β1 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-β1 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.
摘要：
动脉硬化是导致年龄相关心血管疾病发病率指数上升的关键危险因素。这个过程涉及年龄诱导的动脉促炎，胶原蛋白沉积，钙化,共同导致动脉硬化。导致胶原在动脉壁中沉积的促炎过程的主要驱动因素是转化生长因子-β1(TGF-β1)信号传导。这种信号的激活在驱动血管细胞外重塑中至关重要，最终导致动脉纤维化和钙化。有趣的是,糖基化蛋白血管蛋白（VASN）与TGF-β1物理相互作用，并在功能上抑制其在动脉壁和血管平滑肌细胞（VSMC）中的促炎纤维化信号。值得注意的是,随着年龄的增长，II型基质金属蛋白酶（MMP-2）被激活，有效切割动脉壁和VSMC中的VASN蛋白。这种年龄相关/MMP-2介导的VASN水平降低加剧了TGF-β1的激活，在动脉壁放大动脉纤维化和钙化。重要的是,TGF-β1是血管紧张素Ⅱ(AngⅡ)信号通路在动脉壁和血管平滑肌细胞中的下游分子,由VASN调制。的确,对年轻大鼠长期服用AngII可显着激活MMP-2，并将VASN表达降低至与未治疗的老年对照大鼠相当的水平。这篇综述强调并讨论了VASN通过减轻动脉壁和VSMC中的TGF-β1激活和信号传导在减轻纤维化和钙化中的作用。了解这些分子物理和功能相互作用可能为建立基于VASN的治疗策略以抵消不良年龄相关的心血管重塑铺平道路。最终降低心血管疾病的风险。
