miR-27b controls venous specification and tip cell fate

Blood - Tập 119 - Trang 2679-2687 - 2012
Dauren Biyashev1,2, Dorina Veliceasa1, Jacek Topczewski3, Jolanta M. Topczewska3, Igor Mizgirev4,5, Elena Vinokour1, Alagarsamy L. Reddi6, Jonathan D. Licht6,7, Sergei Y. Revskoy4,7, Olga V. Volpert1,7
1Urology Department, Northwestern University Feinberg School of Medicine, Chicago, IL
2Feinberg Cardiovascular Research Institute, Chicago, IL
3Department of Pediatrics, Children's Memorial Research Center, Northwestern University Feinberg School of Medicine, Chicago, IL
4Department of Medicine, Division of Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL
5Petrov Research Oncology Institute, St Petersburg, Russia
6Department of Medicine, Division of Hematology-Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL
7Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL;

Tóm tắt

Abstract We discovered that miR-27b controls 2 critical vascular functions: it turns the angiogenic switch on by promoting endothelial tip cell fate and sprouting and it promotes venous differentiation. We have identified its targets, a Notch ligand Delta-like ligand 4 (Dll4) and Sprouty homologue 2 (Spry2). miR-27b knockdown in zebrafish and mouse tissues severely impaired vessel sprouting and filopodia formation. Moreover, miR-27b was necessary for the formation of the first embryonic vein in fish and controlled the expression of arterial and venous markers in human endothelium, including Ephrin B2 (EphB2), EphB4, FMS-related tyrosine kinase 1 (Flt1), and Flt4. In zebrafish, Dll4 inhibition caused increased sprouting and longer intersegmental vessels and exacerbated tip cell migration. Blocking Spry2 caused premature vessel branching. In contrast, Spry2 overexpression eliminated the tip cell branching in the intersegmental vessels. Blockade of Dll4 and Spry2 disrupted arterial specification and augmented the expression of venous markers. Blocking either Spry2 or Dll4 rescued the miR-27b knockdown phenotype in zebrafish and in mouse vascular explants, pointing to essential roles of these targets downstream of miR-27b. Our study identifies critical role of miR-27b in the control of endothelial tip cell fate, branching, and venous specification and determines Spry2 and Dll4 as its essential targets.

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Blood

Tập 119

2679-2687

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