Institute of Cardiovascular Regeneration, Center of Molecular Medicine (A.T., L.S.T., A.F., M.M.-R., L.R.V., B.N.T., J.N., S.F.G., M.M., D.R.M., B.S., W.T.A., D.J., S.D., G.L.), Goethe University Frankfurt, Germany.
Cardiopulmonary Institute (A.T., L.S.T., S.F.G., M.M., S.K., B.S., S.G., W.T.A., D.J., I.F., N.W., S.D., G.L.), Goethe University Frankfurt, Germany.
Circ Res. 2024 May 10;134(10):1240-1255. doi: 10.1161/CIRCRESAHA.123.324183. Epub 2024 Apr 2.
Pericytes are capillary-associated mural cells involved in the maintenance and stability of the vascular network. Although aging is one of the main risk factors for cardiovascular disease, the consequences of aging on cardiac pericytes are unknown.
In this study, we have combined single-nucleus RNA sequencing and histological analysis to determine the effects of aging on cardiac pericytes. Furthermore, we have conducted in vivo and in vitro analysis of RGS5 (regulator of G-protein signaling 5) loss of function and finally have performed pericytes-fibroblasts coculture studies to understand the effect of RGS5 deletion in pericytes on the neighboring fibroblasts.
Aging reduced the pericyte area and capillary coverage in the murine heart. Single-nucleus RNA sequencing analysis further revealed that the expression of was reduced in cardiac pericytes from aged mice. In vivo and in vitro studies showed that the deletion of RGS5 impaired cardiac function, induced fibrosis, and morphological changes in pericytes characterized by a profibrotic gene expression signature and the expression of different ECM (extracellular matrix) components and growth factors, for example, and . Indeed, culturing fibroblasts with the supernatant of RGS5-deficient pericytes induced their activation as evidenced by the increased expression of αSMA (alpha smooth muscle actin) in a TGFβ (transforming growth factor beta)2-dependent mechanism.
Our results have identified RGS5 as a crucial regulator of pericyte function during cardiac aging. The deletion of RGS5 causes cardiac dysfunction and induces myocardial fibrosis, one of the hallmarks of cardiac aging.
周细胞是与毛细血管相关的壁细胞，参与维持和稳定血管网络。尽管衰老是心血管疾病的主要危险因素之一，但衰老对心脏周细胞的影响尚不清楚。
在这项研究中，我们结合了单细胞 RNA 测序和组织学分析来确定衰老对心脏周细胞的影响。此外，我们还进行了 RGS5（G 蛋白信号调节因子 5）功能丧失的体内和体外分析，最后进行了周细胞-成纤维细胞共培养研究，以了解周细胞中 RGS5 缺失对邻近成纤维细胞的影响。
衰老减少了小鼠心脏中的周细胞面积和毛细血管覆盖率。单细胞 RNA 测序分析进一步表明，衰老小鼠心脏周细胞中 的表达减少。体内和体外研究表明，RGS5 的缺失损害了心脏功能，诱导了纤维化，并使周细胞发生形态变化，其特征是表达促纤维化基因特征和不同的细胞外基质（ECM）成分和生长因子，例如 和 。事实上，用缺乏 RGS5 的周细胞的上清液培养成纤维细胞，通过 TGFβ（转化生长因子β）2 依赖性机制诱导其激活，表现为 αSMA（α平滑肌肌动蛋白）的表达增加。
我们的研究结果表明，RGS5 是心脏衰老过程中周细胞功能的关键调节因子。RGS5 的缺失导致心脏功能障碍，并诱导心肌纤维化，这是心脏衰老的标志之一。
