Abstract 14953: STAT3 in Vascular Smooth Muscle Cells Protects Aorta From Dissection by Reinforcing Aortic Wall

Abstract

Aortic dissection (AD) is a common and fatal disease for which pathogenesis is largely unknown. Recently we and others reported that JAK/STAT3-activating cytokines are highly expressed in human and mouse models of AD. In this study, we used a mouse model of AD that was induced by continuous infusion of beta-aminopropionitrile, an inhibitor of lysyl oxidase that cross-links collagen and elastin, and angiotensin II (BAPN+AngII). Mouse AD tissue showed STAT3 activation (phosphorylation) both in inflammatory cells and in vascular smooth muscle cells (VSMCs). We used the smooth muscle-specific knockout mice for SOCS3, a negative feedback regulator of STAT3 (smSOCS3-KO), to activate STAT3 specifically in VSMCs. smSOCS3-KO mice developed less severe AD in the aortic arch (WT; 0.093±0.018 vs. smSOCS3-KO; 0.018±0.013 mm/g body weight, P=0.014), as determined by the lesion length. Immunofluorescence staining showed phospho-STAT3 in medial VSMCs by BAPN+AngII, which was more prominent in smSOCS3-KO as expected. Interestingly, smSOCS3-KO aorta showed more collagen fibers, suggesting that STAT3 activation in VSMCs may augment the tensile strength of aorta. Indeed, direct measurement of the tensile strength of the excised aortic rings indicated that smSOCS3-KO aorta had more tensile strength compared to wild type aorta (WT; 0.171±0.018 vs. smSOCS3-KO; 0.234±0.011 N/mm, P=0.004). Consistently, adventitia of smSOCS3-KO aorta showed more fibroblasts, as determined by ER-TR7 staining, compared to WT aorta. We also examined surgical specimens from AD patients for phospho-STAT3 and collagen deposition. Strong signal of phospho-STAT3 was detected at the site of dissection. However, phospho-STAT3 was reduced where strong collagen deposition was observed, suggesting that STAT3 activity is reduced after the completion of collagen deposition. From these results we concluded that activation of STAT3 in VSMCs reinforces aortic wall by enhancing collagen deposition, thus protecting aorta from dissection. Understanding of the protection mechanism of the aortic walls from dissection would lead to better understanding of the molecular pathogenesis, which is essential for developing novel therapeutic strategy for AD.