Reducing the high incidence of hypertension-related cardiovascular diseases is an important strategy for the optimal treatment of hypertension. Vascular remodeling, characterized by increased lumen size and thickened media with increased collagen deposition, is a typical feature of end-organ damage from hypertension, contributing to clinical morbidity and mortality. [1][2][3] One of the causal factors for vascular remodeling is angiotensin II (Ang II), a key effector of the renin-angiotensin system. Studies have indicated that in addition to its roles in vasoconstriction and retention of sodium and water, causing hypertension, Ang II is also involved in stimulating vascular smooth muscle cell (VSMC) contraction, augmenting cell growth, increasing deposition of extracellular matrix, inducing cell migration, and promoting inflammation and oxidative stress, ultimately leading to vascular hypertrophy, fibrosis, and remodeling. [4][5][6] Increased knowledge of the downstream signaling cascades of Ang II-induced hypertension and vascular remodeling is needed if effective clinical interventions are to be developed.The cellular repressor of E1A-stimulated genes (CREG) is a novel secreted glycoprotein associated broadly with diverse cellular processes. 7,8 CREG is ubiquitously expressed in mature tissues and cells in mammals and is expressed at low levels in immature cells, such as pluripotent mouse embryonic stem cells, human embryonic carcinoma cells, and synthetic phenotypic VSMCs. [8][9][10] In embryos 9.5 days post-coitum, CREG expression emerges at the beginning of vascular development when vessels comprise only a monolayer of cells. With advanced differentiation, CREG was expressed continuously not only in endomembranes and the vascular tunica media, but also in adventitia until 18.5 days post-coitum.11 Interestingly, studies of CREG have revealed that CREG levels were greatly reduced in the arteries after vascular injury, whereas forced expression of CREG attenuates proliferation and dedifferentiation of VSMCs, and neointimal formation, 8,[12][13][14][15] Objective-Cellular repressor of E1A-stimulated genes (CREG) is a lysosomal glycoprotein implicated in maintaining vascular homeostasis. Here, we have hypothesized that CREG is a critical target of intervention for the prevention of hypertensive vascular remodeling. Approach and Results-CREG gene expression was significantly decreased accompanied by an upregulated expression of angiotensin II (Ang II) in remodeled vascular tissues of high salt-induced Dahl salt-sensitive rats and Ang II-induced mice. In particular, the downregulation of CREG gene was Ang II specific and independent from blood pressure. Prominent medial hypertrophy and vascular fibrosis in both thoracic aortas and mesenteric arteries were observed in CREG +/− mice infused with Ang II than in CREG +/+ mice, but blunted response in CREG +/+ mice received recombinant human CREG protein, suggesting that changes in CREG expression account for the different phenotype between genotypes. Within a tiled ...
