MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis

Abstract

Within the circulatory system, blood flow regulates vascular remodeling1, stimulates blood stem cell formation2, and plays a role in the pathology of vascular disease3. During vertebrate embryogenesis, vascular patterning is initially guided by conserved genetic pathways that act prior to circulation4. Subsequently, endothelial cells must incorporate the mechanosensory stimulus of blood flow with these early signals to shape the embryonic vascular system4. However, few details are known about how these signals are integrated during development. To investigate this process, we focused on the aortic arch (AA) blood vessels, which are known to remodel in response to blood flow1. By using 2-photon imaging of live zebrafish embryos, we observe that flow is essential for angiogenesis during AA development. We further find that angiogenic sprouting of AA vessels requires a flow-induced genetic pathway in which the mechano-sensitive zinc finger transcription factor klf2a5-7 induces expression of an endothelial-specific microRNA, mir-126, to activate Vegf signaling. Taken together, our work describes a novel genetic mechanism in which a microRNA facilitates integration of a physiological stimulus with growth factor signaling in endothelial cells to guide angiogenesis.

FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation

“…Our study shows that degradation of KLF2 by FBW7 is indispensable for angiogenesis in mice. Moreover, Klf2 is essential for normal valve development [56] and flow-induced angiogenesis during aortic arch development by regulating the expression of miR126 in zebrafish [12]. Our data showed that zebrafish Klf2 is also a target of zebrafish Fbw7.…”

“…Several KLFs, including KLF2, 4, 6, 10, and 15, have been reported to be involved in vascular functions [7][8][9][10][11]. Among them, KLF2 (also known as LKLF) is a central regulator of endothelial functions, including angiogenesis, inflammation, thrombosis and vascular tone [7,12]. A KLF2 deficiency impairs endothelial barrier integrity and increases endothelial leakage by regulating the expression of the key junction protein occludin [7,13].…”

Endothelial microRNA-150 is an intrinsic suppressor of pathologic ocular neovascularization

“…MiRNAs play critical roles in many biological processes, such as cell proliferation, cell death, neuronal differentiation and development, and angiogenesis (8)(9)(10)(11). Moreover, dysregulation of miRNA is associated with many diseases, such as cancer and heart diseases, and are being developed as important biomarkers (12,13). In neovascular diseases, both pro-and antiangiogenic miRNAs were identified in vascular ECs and perivascular cells (8,13,14).…”

Combinatory action of VEGFR2 and MAP kinase pathways maintains endothelial-cell integrity

“…In PP1-treated embryos, both the dorsal aorta and cardinal vein were narrower, with Figure S3). To rule out the possibility that the absence of blood flow and blood pressure could lead to collapse of vascular lumens, a myosin-ATPase inhibitor BDM (2, 3-butanedione 2-monoxime) was used to stop the heart beat of 3 dpf zebrafish embryos [13]. After incubation of embryos in BDM for 24 h, vascular lumen appeared intact in the absence of heart beat (Supplementary information, Figure S4).…”