Objective-Bone marrow-derived progenitor cells have been implicated to contribute to neointima formation, but the time course and extent of their accumulation and differentiation into vascular cells and, most importantly, the long-term contribution of bone marrow-derived progenitor cells to the vascular lesion remain undefined. Methods and Results-Wire-induced injury of the femoral artery was performed on chimeric C57BL/6 mice transplanted with bone marrow from transgenic mice expressing enhanced green fluorescence protein, and vessels were harvested at 3 days, 1, 2, 3, 4, 6, and 16 weeks after dilatation (nϭ8 animals per time point). Using high-resolution microscopy, we unexpectedly found that the expression of smooth muscle cell or endothelial cell markers in enhanced green fluorescence protein positive cells was a very rare event. Indeed, most of the enhanced green fluorescence protein positive cells that accumulated during the acute inflammatory response were identified as monocytes/macrophages, and their number declined at later time points. In contrast, a substantial fraction of highly proliferative stem cell antigen-1 and CD34 ϩ but enhanced green fluorescence protein negative and thus locally derived cells were detected in the adventitia. Conclusion-These data provide evidence that the differentiation of bone marrow-derived progenitor cells into smooth muscle cell or endothelial cell lineages seems to be an exceedingly rare event. Moreover, the contribution of bone marrow-derived cells to the cellular compartment of the neointima is limited to a transient period of the inflammatory response. Key Words: progenitor cells Ⅲ smooth muscle cells Ⅲ vascular remodeling Ⅲ restenosis Ⅲ inflammation S mooth muscle cells (SMCs) play a decisive role in the pathogenesis of vascular diseases and its clinical manifestations. In addition to atherosclerosis, neointima (NI) formation is a major burden in vascular medicine and concerns patients after percutaneous coronary intervention, bypass operation, or graft vasculopathy. It had been widely accepted that intimal SMCs in proliferative vascular diseases are derived from resident medial SMCs or adventitial fibroblasts. 1,2 Several years ago, this theory was challenged by the suggested ability of bone marrow-derived progenitor cells (BMPCs) to differentiate into vascular cells during arterial remodeling. 3 However, until today, the differentiation capacity of BMPCs in vivo remains highly controversial. 4 In different mouse models of atherosclerotic plaque formation, it has been shown very recently that SMCs and endothelial cells (ECs) in atherosclerotic plaques are exclusively derived from the local vessel wall and not from the circulating blood. 5,6 See accompanying article on page 1877Although the homing of BM-derived cells on mechanically injured vessels has been clearly demonstrated in various animal models, the fraction of these cells expressing ␣-smooth muscle actin (␣-SMA) showed wide diversity, ranging from negligible to substantial numbers of all vascular SMCs. 3,...

BackgroundThe phosphatase PTEN represents an important physiological inhibitor of phosphatidylinositol-3 kinase (PI3-K)/protein kinase B (Akt) signalling, however, the functional role of PTEN in the initial phase of angioplasty-induced vascular injury remains elusive. In the present study we sought to determine PTEN's effect on vascular smooth muscle cell (VSMC) apoptosis following acute injury in vivo and in vitro.Methods and ResultsImmunohistochemistry indicated a faint basal expression and equal distribution of PTEN in uninjured rat carotid arteries. 12 h following balloon-injury, PTEN expression was strongly increased in apoptotic (TUNEL+) VSMC. In vitro, stimulation with serum or different growth factors or subjecting VSMC to cyclic stretch had no effect on PTEN expression, whereas stimulation with H2O2 robustly increased PTEN expression in a time- and dose-dependent manner. To evaluate the functional role of PTEN expression, human VSMC were transduced with WT-PTEN. Overexpression of PTEN increased the number of apoptotic VSMC (19.8%±4.4 vs. 5.6%±2.3; P<0.001) as determined by TUNEL assay. In contrast, siRNA-mediated knock-down of PTEN attenuated the basal as well as H2O2-induced apoptosis of VSMC. Mechanistically, overexpression of PTEN prevented serum-induced Akt-phosphorylation, whereas siRNA-mediated knock down of PTEN augmented Akt-activation. Moreover, co-transfection of PTEN and a constitutive active Akt mutant prevented PTEN-dependent augmentation of VSMC apoptosis, indicating, that PTEN regulates VSMC apoptosis by inhibition of Akt phosphorylation/activation.ConclusionBy interfering with the PI3-K/Akt-dependent survival signalling, the oxidative stress-induced up regulation of PTEN in VSMC of injured arteries augments the sensitivity of VSMC to apoptotic stimuli in the early phase following vascular injury, augmenting the initial injury and cell loss of the injured vessel wall. Thus, these data add to our understanding of PTEN's role during vascular remodelling.

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