The basic helix-loop-helix transcription factor, dHAND, is required for vascular development
Hiroyuki Yamagishi, … , Eric N. Olson, Deepak Srivastava
Hiroyuki Yamagishi, … , Eric N. Olson, Deepak Srivastava
Published February 1, 2000
Citation Information: J Clin Invest. 2000;105(3):261-270. https://doi.org/10.1172/JCI8856.
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Article

The basic helix-loop-helix transcription factor, dHAND, is required for vascular development

Abstract

Reciprocal interactions between vascular endothelial cells and vascular mesenchymal cells are essential for angiogenesis. Here we show that the basic helix-loop-helix transcription factor, dHAND/Hand2, is expressed in the developing vascular mesenchyme and its derivative, vascular smooth muscle cells (VSMCs). Targeted deletion of the dHAND gene in mice revealed severe defects of embryonic and yolk sac vascular development by embryonic day 9.5. Vascular endothelial cells expressed most markers of differentiation. Vascular mesenchymal cells migrated appropriately but failed to make contact with vascular endothelial cells and did not differentiate into VSMCs. In a screen for genes whose expression was dependent upon dHAND (using subtractive hybridization comparing wild-type and dHAND-null hearts), the VEGF165 receptor, neuropilin-1, was found to be downregulated in dHAND mutants. These results suggest that dHAND is required for vascular development and regulates angiogenesis, possibly through a VEGF signaling pathway.

Authors

Hiroyuki Yamagishi, Eric N. Olson, Deepak Srivastava

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Endothelial development in dHAND mutants. Whole-mount immunochemistry re...
Endothelial development in dHAND mutants. Whole-mount immunochemistry revealed that endothelial cells expressed PECAM-1 protein appropriately in wild-type (a) and mutant (b) E9.5 embryos, but displayed a disorganized pattern in dHAND mutants (b). The rostral portion of dHAND-null embryos was more severely affected than the caudal region, where the aorta (ao) and somitic arteries (arrowheads) were visible. Sagittal section of PECAM-1 antibody–stained wild-type (e) and mutant (f) embryos revealed disorganization of the dorsal aorta of dHAND-null embryos, where the aortic lumen was evident. Note patency of the aortic arch artery (aa) in the mutant (f). β-galactosidase activity in wild type (c) and mutant (d) embryos harboring lacZ under control of the Tie2 promoter revealed disorganization of lacZ expression in dHAND-null embryos compared with wild-type embryos. Transverse sections of wild-type (g) and mutant (h) embryos in the caudal region demonstrate the dilated nature of caudal vessels of dHAND-null embryos. ht, heart; as, aortic sac; h, head; nt, neural tube; fg, foregut.