Objective-Vascular smooth muscle cells (VSMCs) contribute significantly to occlusive vascular diseases by virtue of their ability to switch to a noncontractile, migratory, and proliferating phenotype. Although the participation of ion channels in this phenotypic modulation (PM) has been described previously, changes in their expression are poorly defined because of their large molecular diversity. We obtained a global portrait of ion channel expression in contractile versus proliferating mouse femoral artery VSMCs, and explored the functional contribution to the PM of the most relevant changes that we observed. Methods and Results-High-throughput real-time polymerase chain reaction of 87 ion channel genes was performed in 2 experimental paradigms: an in vivo model of endoluminal lesion and an in vitro model of cultured VSMCs obtained from explants. mRNA expression changes showed a good correlation between the 2 proliferative models, with only 2 genes, Kv1.3 and Kv␤2, increasing their expression on proliferation. The functional characterization demonstrates that Kv1.3 currents increased in proliferating VSMC and that their selective blockade inhibits migration and proliferation. Key Words: gene expression Ⅲ ion channels Ⅲ restenosis Ⅲ vascular biology Ⅲ vascular muscle Ⅲ Kv1.3 channels Ⅲ vascular remodeling V ascular smooth muscle cells (VSMCs) are differentiated cells that regulate vessel diameter and determine tissue perfusion. However, they can exhibit a variety of functionally dissimilar phenotypes. In response to local cues, VSMCs experience a phenotypic modulation (PM), with profound and reversible changes leading to proliferation, migration, and secretion of extracellular matrix components. 1 This plasticity is essential for injury repair, but it also contributes to the development and progression of vascular disease in response to abnormal environmental signals. It is becoming evident that contractile and proliferative phenotypes represent extreme cases of a spectrum of phenotypes that may coexist as the result of a developmentally regulated genetic program constantly modulated by environmental cues. This explains both a relatively stable expression of certain transcriptional programs in different VSMCs and a marked plasticity of these cells, including the ability to respond with different genetic programs to readjust cellular activity to mechanical and hormonal factors. [1][2][3] See accompanying article on page 1073 Conclusion-TheseThe switch in ion transport mechanisms associated with PM is getting increasing amounts of attention. Coordinate changes in ion channels are an integral component of VSMC plasticity, as they can redirect biochemical activity toward new functional responses. 4,5 Moreover, both contractile and proliferative signals require specific changes in intracellular [Ca 2ϩ ] and membrane potential that are determined by the ion channels expressed in VSMCs. Remodeling of several ion channels has shown to be functionally important for the PM of VSMCs in several preparations. [5][6][7][8]...

Angiotensin-II–driven calcineurin activation and regulator of calcineurin-1 (Rcan-1) expression is required for pathological vascular remodeling in mice.

Rationale Activin receptor-Like Kinase-1 (ALK1) is an endothelial TGF-β receptor involved in angiogenesis. ALK1 expression is high in the embryo vasculature, becoming less detectable in the quiescent endothelium of adult stages. However, ALK1 expression becomes rapidly increased after angiogenic stimuli such as vascular injury. Objective To characterize the molecular mechanisms underlying the regulation of ALK1 upon vascular injury. Methods and Results Alk1 becomes strongly upregulated in endothelial (EC) and vascular smooth muscle cells (vSMC) of mouse femoral arteries after wire-induced endothelial denudation. In vitro, denudation of monolayers of Human Umbilical Vein Endothelial Cells (HUVEC) also leads to an increase in ALK1. Interestingly, a key factor in tissue remodeling, Krüppel-like factor 6 (KLF6), translocates to the cell nucleus during wound healing, concomitantly with an increase in the ALK1 gene transcriptional rate. KLF6 knock down in HUVECs promotes ALK1 mRNA downregulation. Moreover, Klf6+/− mice have lower levels of Alk1 in their vasculature compared with their wild type siblings. Chromatin immunoprecipitation assays show that KLF6 interacts with ALK1 promoter in ECs, and this interaction is enhanced during wound healing. We demonstrate that KLF6 is transactivating ALK1 gene, and this transactivation occurs by a synergistic cooperative mechanism with Sp1. Finally, Alk1 levels in vSMCs are not directly upregulated in response to damage, but in response to soluble factors, such as IL-6, released from ECs after injury. Conclusions ALK1 is upregulated in ECs during vascular injury by a synergistic cooperative mechanism between KLF6 and Sp1, and in vSMCs by an EC-vSMC paracrine communication during vascular remodeling.