Center for Cardiovascular Research and The Heart Center, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA; Molecular, Cellular and Developmental Biology Program, The Ohio State University, Columbus, OH, USA.
Department of Mechanical and Aerospace Engineering, The Ohio State University, Columbus, OH, USA.
Vascul Pharmacol. 2022 Aug;145:107087. doi: 10.1016/j.vph.2022.107087. Epub 2022 Jul 2.
Notch signaling is an evolutionarily conserved pathway that functions via direct cell-cell contact. The Notch ligand Jagged1 (Jag1) has been extensively studied in vascular development, particularly for its role in smooth muscle cell maturation. Endothelial cell-expressed Jag1 is essential for blood vessel formation by signaling to nascent vascular smooth muscle cells and promoting their differentiation. Given the established importance of Jag1 in endothelial cell/smooth muscle crosstalk during development, we sought to determine the extent of this communication in the adult vasculature for blood vessel function and homeostasis.
We conditionally deleted Jag1 in endothelial cells of adult mice and examined the phenotypic consequences on smooth muscle cells of the vasculature.
Our results show that genetic loss of Jag1 in endothelial cells has a significant impact on Notch signaling and vascular smooth muscle function in mature blood vessels. Endothelial cell-specific deletion of Jag1 causes a concomitant loss of JAG1 and NOTCH3 expression in vascular smooth muscle cells, resulting in a transition to a less differentiated state. Aortic vascular smooth muscle cells isolated from the endothelial cell-specific Jag1 deficient mice retain an altered phenotype in culture with fixed changes in gene expression and reduced Notch signaling. Utilizing comparative RNA-sequence analysis, we found that Jag1 deficiency preferentially affects extracellular matrix and adhesion protein gene expression. Vasoreactivity studies revealed a reduced contractile response and impaired agonist-induced relaxation in endothelial cell Jag1-deficient aortas compared to controls.
These data are the first to demonstrate that Jag1 in adult endothelial cells is required for the regulation and homeostasis of smooth muscle cell function in arterial vessels partially through the autoregulation of Notch signaling and cell matrix/adhesion components in smooth muscle cells.
Notch 信号通路是一种进化上保守的途径，通过直接的细胞间接触发挥作用。Notch 配体 Jagged1（Jag1）在血管发育中得到了广泛研究，尤其是其在平滑肌细胞成熟中的作用。内皮细胞表达的 Jag1 通过向新生血管平滑肌细胞发出信号并促进其分化，对于血管形成至关重要。鉴于 Jag1 在发育过程中内皮细胞/平滑肌细胞相互作用中的重要作用，我们试图确定这种通讯在成年脉管系统中的程度，以维持血管功能和稳态。
我们在成年小鼠的内皮细胞中条件性缺失 Jag1，并检查其对血管平滑肌细胞的表型后果。
我们的结果表明，内皮细胞中 Jag1 的遗传缺失对成熟血管中的 Notch 信号和血管平滑肌功能有显著影响。内皮细胞特异性缺失 Jag1 导致血管平滑肌细胞中 JAG1 和 NOTCH3 表达的同时丢失，导致向更不成熟的状态转变。从内皮细胞特异性 Jag1 缺陷小鼠分离的主动脉血管平滑肌细胞在培养中保留改变的表型，基因表达固定变化，Notch 信号降低。利用比较 RNA 测序分析，我们发现 Jag1 缺失优先影响细胞外基质和黏附蛋白的基因表达。血管反应性研究表明，与对照组相比，内皮细胞 Jag1 缺陷的主动脉的收缩反应降低，激动剂诱导的松弛受损。
这些数据首次表明，成年内皮细胞中的 Jag1 对于调节和维持动脉血管平滑肌细胞功能的稳态是必需的，部分通过 Notch 信号的自调节以及平滑肌细胞中的细胞基质/黏附成分。
