Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK (Y.-C.H., X.G., R.V., K.S., Z.J.A.-N., J.K., R.S., L.C., B.C., L.X., F.L., L.E.O., J.A., R.S.S.).
Now with Sanegene Bio, Woburn, MA (X.G.).
Circ Res. 2023 Sep;133(6):463-480. doi: 10.1161/CIRCRESAHA.123.323027. Epub 2023 Aug 9.
Cardiac valve disease is observed in 2.5% of the general population and 10% of the elderly people. Effective pharmacological treatments are currently not available, and patients with severe cardiac valve disease require surgery. PROX1 (prospero-related homeobox transcription factor 1) and FOXC2 (Forkhead box C2 transcription factor) are transcription factors that are required for the development of lymphatic and venous valves. We found that PROX1 and FOXC2 are expressed in a subset of valvular endothelial cells (VECs) that are located on the downstream (fibrosa) side of cardiac valves. Whether PROX1 and FOXC2 regulate cardiac valve development and disease is not known.
We used histology, electron microscopy, and echocardiography to investigate the structure and functioning of heart valves from mice in which was conditionally deleted from VECs. Isolated valve endothelial cells and valve interstitial cells were used to identify the molecular mechanisms in vitro, which were tested in vivo by RNAScope, additional mouse models, and pharmacological approaches. The significance of our findings was tested by evaluation of human samples of mitral valve prolapse and aortic valve insufficiency.
Histological analysis revealed that the aortic and mitral valves of mice become progressively thick and myxomatous. Echocardiography revealed that the aortic valves of mice are stenotic was downregulated and PDGF-B (platelet-derived growth factor-B) was upregulated in the VECs of mice. Conditional knockdown of FOXC2 and conditional overexpression of PDGF-B in VECs recapitulated the phenotype of mice. PDGF-B was also increased in mice lacking FOXC2 and in human mitral valve prolapse and insufficient aortic valve samples. Pharmacological inhibition of PDGF-B signaling with imatinib partially ameliorated the valve defects of mice.
PROX1 antagonizes PDGF-B signaling partially via FOXC2 to maintain the extracellular matrix composition and prevent myxomatous degeneration of cardiac valves.
心脏瓣膜疾病在普通人群中占 2.5%，在老年人中占 10%。目前尚无有效的药物治疗方法，严重心脏瓣膜疾病患者需要手术治疗。PROX1（prospero 相关同源盒转录因子 1）和 FOXC2（叉头框 C2 转录因子）是发育淋巴管和静脉瓣膜所必需的转录因子。我们发现 PROX1 和 FOXC2 表达于位于心脏瓣膜下游（纤维层）的一组瓣膜内皮细胞（VEC）中。PROX1 和 FOXC2 是否调节心脏瓣膜发育和疾病尚不清楚。
我们使用组织学、电子显微镜和超声心动图来研究条件性从 VEC 中缺失的 小鼠的心脏瓣膜的结构和功能。分离的瓣膜内皮细胞和瓣膜间质细胞用于体外鉴定分子机制，并通过 RNAScope、其他小鼠模型和药理学方法在体内进行测试。通过评估二尖瓣脱垂和主动脉瓣关闭不全的人类样本来检验我们发现的意义。
组织学分析显示， 小鼠的主动脉瓣和二尖瓣逐渐变厚并出现黏液样变性。超声心动图显示， 小鼠的主动脉瓣狭窄，VEC 中的 PROX1 表达下调，PDGF-B（血小板衍生生长因子-B）上调。VEC 中 FOXC2 的条件性敲低和 PDGF-B 的条件性过表达可再现 小鼠的表型。FOXC2 缺失的小鼠和人类二尖瓣脱垂及主动脉瓣关闭不全样本中 PDGF-B 也增加。用伊马替尼抑制 PDGF-B 信号可部分改善 小鼠的瓣膜缺陷。
PROX1 通过 FOXC2 拮抗 PDGF-B 信号，部分维持细胞外基质组成，防止心脏瓣膜黏液样变性。
