Ng Ann, Wong Michelle, Viviano Beth, Erlich Jonathan M, Alba George, Pflederer Camila, Jay Patrick Y, Saunders Scott
Department of Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, MO 63110, USA.
Dev Biol. 2009 Nov 1;335(1):208-15. doi: 10.1016/j.ydbio.2009.08.029. Epub 2009 Sep 4.
Glypican-3 (Gpc3) is a heparan sulfate proteoglycan (HSPG) expressed widely during vertebrate development. Loss-of-function mutations cause Simpson-Golabi-Behmel syndrome (SGBS), a rare and complex congenital overgrowth syndrome with a number of associated developmental abnormalities including congenital heart disease. We found that Gpc3-deficient mice display a high incidence of congenital cardiac malformations like ventricular septal defects, common atrioventricular canal and double outlet right ventricle. In addition we observed coronary artery fistulas, which have not been previously reported in SGBS. Coronary artery fistulas are noteworthy because little is known about the molecular basis of this abnormality. Formation of the coronary vascular plexus in Gpc3-deficient embryos was delayed compared to wild-type, and consistent with GPC3 functioning as a co-receptor for fibroblast growth factor-9 (FGF9), we found a reduction in Sonic Hedgehog (Shh) mRNA expression and signaling in embryonic mutant hearts. Interestingly, we found an asymmetric reduction in SHH signaling in cardiac myocytes, as compared with perivascular cells, resulting in excessive coronary artery formation in the Gpc3-deficient animals. We hypothesize that the excessive development of coronary arteries over veins enables the formation of coronary artery fistulas. This work has broad significance to understanding the genetic basis of coronary development and potentially to molecular mechanisms relevant to revascularization following ischemic injury to the heart.
磷脂酰肌醇蛋白聚糖-3（Gpc3）是一种硫酸乙酰肝素蛋白聚糖（HSPG），在脊椎动物发育过程中广泛表达。功能丧失性突变会导致辛普森-戈拉比-贝梅尔综合征（SGBS），这是一种罕见且复杂的先天性过度生长综合征，伴有许多相关的发育异常，包括先天性心脏病。我们发现，Gpc3基因缺陷的小鼠表现出高发性先天性心脏畸形，如室间隔缺损、房室管共同通道和右心室双出口。此外，我们还观察到冠状动脉瘘，这在SGBS中此前尚未有报道。冠状动脉瘘值得关注，因为人们对这种异常的分子基础知之甚少。与野生型相比，Gpc3基因缺陷胚胎中冠状血管丛的形成延迟，并且与GPC3作为成纤维细胞生长因子-9（FGF9）的共受体发挥作用一致，我们发现胚胎突变心脏中 Sonic Hedgehog（Shh）mRNA表达和信号传导减少。有趣的是，与血管周围细胞相比，我们发现心肌细胞中SHH信号传导存在不对称减少，导致Gpc3基因缺陷动物中冠状动脉过度形成。我们推测，冠状动脉相对于静脉的过度发育促使了冠状动脉瘘的形成。这项工作对于理解冠状动脉发育的遗传基础以及潜在地对于与心脏缺血性损伤后血管重建相关的分子机制具有广泛意义。
