SOX7 deficiency causes ventricular septal defects through its effects on endocardial-to-mesenchymal transition and the expression of Wnt4 and Bmp2.

SOX7 is a transcription factor-encoding gene located in a region on chromosome 8p23.1 that is recurrently deleted in individuals with ventricular septal defects (VSDs). We have previously shown that Sox7-/- embryos die of heart failure around E11.5. Here, we demonstrate that these embryos have hypocellular endocardial cushions with severely reduced numbers of mesenchymal cells. Ablation of Sox7 in the endocardium also resulted in hypocellular endocardial cushions, and we observed VSDs in rare E15.5 Sox7flox/-;Tie2-Cre and Sox7flox/flox;Tie2-Cre embryos that survived to E15.5. In atrioventricular explant studies, we showed that SOX7 deficiency leads to a severe reduction in endocardial-to-mesenchymal transition (EndMT). RNA-seq studies performed on E9.5 Sox7-/- heart tubes revealed severely reduced Wnt4 transcript levels. Wnt4 is expressed in the endocardium and promotes EndMT by acting in a paracrine manner to increase the expression of Bmp2 in the myocardium. Both WNT4 and BMP2 have been previously implicated in the development of VSDs in individuals with 46,XX sex reversal with dysgenesis of kidney, adrenals and lungs (SERKAL) syndrome and in individuals with short stature, facial dysmorphism and skeletal anomalies with or without cardiac anomalies 1 (SSFSC1) syndrome, respectively. We now show that Sox7 and Wnt4 interact genetically in the development of VSDs through their additive effects on endocardial cushion development with Sox7+/-;Wnt4+/- double heterozygous embryos having hypocellular endocardial cushions and perimembranous and muscular VSDs not seen in their Sox7+/- and Wnt4+/- littermates. These results provide additional evidence that SOX7, WNT4 and BMP2 function in the same pathway during mammalian septal development and that their deficiency can contribute to the development of VSDs in humans.

Location of cerebral atherosclerosis: Why is there a difference between East and West?

Intracranial atherosclerosis is more prevalent in Asian patients, whereas extracranial atherosclerosis is more common in individuals from western countries. The reasons for this discrepancy remain unknown. We reviewed the relevant literature and discussed the currently available information. Although the study population, diagnostic modality, and risk factor definitions differ between studies, hypercholesterolemia is more correlated with extracranial atherosclerosis than intracranial atherosclerosis. The difference in hypercholesterolemia prevalence is one of the main reasons for racial differences. Intracranial arteries contain higher antioxidant level than extracranial arteries and may be more vulnerable to risk factors for antioxidant depletion (e.g., metabolic syndrome and diabetes mellitus). Intracranial arteries may be vulnerable to factors associated with hemodynamic stress (e.g., advanced, salt-retaining hypertension and arterial tortuosity) because of a smaller diameter, thinner media and adventitia, and fewer elastic medial fibers than extracranial arteries. Additionally, non-atherosclerotic arterial diseases (e.g., moyamoya disease) that commonly occur in the intracranial arteries of East Asians may contaminate the reports of intracranial atherosclerosis cases. Genes, including RNF 213 or those associated with high salt sensitivity, may also explain racial differences in atherosclerotic location. To understand racial differences, further well-designed studies on various risk and genetic factors should be performed in patients with cerebral atherosclerosis. Additionally, improvements in diagnostic accuracy via advancements in imaging technologies and increased genetic data will aid in the differentiation of atherosclerosis from non-atherosclerotic intracranial diseases.