OBJECTIVE Pathological vascular remodeling and excessive perivascular fibrosis are major contributors to reduced vessel compliance that exacerbates cardiovascular diseases, for instance, promoting clinically relevant myocardial remodeling. Inflammation plays a significant role in both pathological vascular remodeling and fibrosis. We previously demonstrated that smooth muscle cell-specific PTEN depletion promotes significant vascular fibrosis and accumulation of inflammatory cells. In the current study, we aimed to determine the beneficial role of systemic PTEN elevation on Ang II (angiotensin II)-induced vascular fibrosis and remodeling. Approach and Results: Transgenic mice carrying additional copies of the wild-type Pten gene (super PTEN [sPTEN]) and WT littermates were subjected to Ang II or saline infusion for 14 or 28 days. Compared with WT, Ang II-induced vascular fibrosis was significantly blunted in sPTEN mice, as shown by histochemical stainings and label-free second harmonic generation imaging. The protection against Ang II was recapitulated in sPTEN mice bearing WT bone marrow but not in WT mice reconstituted with sPTEN bone marrow. Ang II-induced elevation of profibrotic and proinflammatory gene expression observed in WT mice was blocked in aortic tissue of sPTEN mice. Immunofluorescent staining and flow cytometry both indicated that perivascular infiltration of T cells and macrophages was significantly inhibited in sPTEN mice. In vitro induction of PTEN expression suppressed Ang II-induced Ccl2 expression in vascular smooth muscle cells. CONCLUSIONS Systemic PTEN elevation mediates protection against Ang II-induced vascular inflammation and fibrosis predominantly through effects in resident vascular cells. Our data highly support that pharmacological upregulation of PTEN could be a novel and viable approach for the treatment of pathological vascular fibrosis.

中文翻译：

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PTEN（磷酸酶和张力蛋白同源物）防止血管紧张素 II（血管紧张素 II）诱导的病理性血管纤维化和重塑-简要报告。

目的 病理性血管重塑和过度的血管周围纤维化是导致血管顺应性降低并加剧心血管疾病的主要因素，例如，促进临床相关的心肌重塑。炎症在病理性血管重塑和纤维化中起重要作用。我们之前证明了平滑肌细胞特异性 PTEN 消耗促进了显着的血管纤维化和炎症细胞的积累。在目前的研究中，我们旨在确定全身 PTEN 升高对 Ang II（血管紧张素 II）诱导的血管纤维化和重塑的有益作用。方法和结果：携带额外的野生型 Pten 基因（超级 PTEN [sPTEN]）拷贝的转基因小鼠和 WT 同窝小鼠接受 Ang II 或盐水输注 14 或 28 天。与 WT 相比，如组织化学染色和无标记二次谐波成像所示，在 sPTEN 小鼠中，Ang II 诱导的血管纤维化显着减弱。对 Ang II 的保护作用在携带 WT 骨髓的 sPTEN 小鼠中得到了概括，但在用 sPTEN 骨髓重组的 WT 小鼠中没有。在 sPTEN 小鼠的主动脉组织中，在 WT 小鼠中观察到的 Ang II 诱导的促纤维化和促炎基因表达的升高被阻断。免疫荧光染色和流式细胞术均表明在 sPTEN 小鼠中 T 细胞和巨噬细胞的血管周围浸润受到显着抑制。PTEN 表达的体外诱导抑制血管平滑肌细胞中Ang II 诱导的Ccl2 表达。结论 全身性 PTEN 升高主要通过对常驻血管细胞的影响介导对 Ang II 诱导的血管炎症和纤维化的保护作用。我们的数据高度支持 PTEN 的药理学上调可能是治疗病理性血管纤维化的一种新颖且可行的方法。