Angiopoietin-like protein 2 regulates endothelial colony forming cell vasculogenesis

Abstract

Angiopoietin-like 2 (ANGPTL2) has been reported to induce sprouting angiogenesis; however, its role in vasculogenesis, the de novo lumenization of endothelial cells (EC), remains unexplored. We sought to investigate the potential role of ANGPTL2 in regulating human cord blood derived endothelial colony forming cell (ECFC) vasculogenesis through siRNA mediated inhibition of ANGPTL2 gene expression. We found that ECFCs in which ANGPTL2 was diminished displayed a 3-fold decrease in in vitro lumenal area whereas addition of exogenous ANGPTL2 protein domains to ECFCs lead to increased lumen formation within a 3 dimensional collagen assay of vasculogenesis. ECFC migration was attenuated by 36% via ANGPTL2 knockdown (KD) although proliferation and apoptosis were not affected. We subsequently found that JNK, but not ERK1/2, phosphorylation was decreased upon ANGPTL2 KD, and expression of MT1-MMP, known to be regulated by JNK and a critical regulator of EC migration and 3D lumen formation, was decreased in lumenized structures in vitro derived from ANGPTL2 silenced ECFCs. Treatment of ECFCs in 3D collagen matrices with either a JNK inhibitor or exogenous rhTIMP-3 (an inhibitor of MT1-MMP activity) resulted in a similar phenotype of decreased vascular lumen formation as observed with ANGPTL2 KD, whereas stimulation of JNK activity increased vasculogenesis. Based on gene silencing, pharmacologic, cellular, and biochemical approaches, we conclude that ANGPTL2 positively regulates ECFC vascular lumen formation likely through its effects on migration and in part by activating JNK and increasing MT1-MMP expression.

19q13.33→qter trisomy in a girl with intellectual impairment and seizures

“…1 D) showed, by in silico analysis using three different algorithms (miRDB ( http://mirdb.org/miRDB/ ), TargetScan ( http://www.targetscan.org/vert_40/ ), and TargetMiner ( http://www.isical.ac.in/~bioinfo_miu/targetminer20.htm )), six possible target genes: EYA4 , S1PR3 , ANGPTL2 , CNTN3 , JMY and PPP1R16 . These genes appear to be related to central nervous system development and brain function, kidney development and disease, as well as vascuologenesis ( Firat-Karalar et al, 2011 , Meng and Lee, 2009 , Richardson et al, 2014 , Shimoda and Watanabe, 2009 ). It is plausible to speculate that the miR-4754 is upregulated in these six patients, due to the trisomic level of the 19q13.4, resulting in these six target genes having their mRNAs and proteins depleted, adding to the patient's phenotype.…”

Systemic influences contribute to prolonged microvascular rarefaction after brain irradiation: a role for endothelial progenitor cells

“…The formation of new cerebral microvessels by bone marrow-derived EPCs may be regulated by both factors within the circulation and mediators produced in the cerebral parenchyma that enhance [e.g., VEGF and Angpt1 (7,14,36,43)] or limit angiogenesis [e.g., endostatin and Thbs1 (7,12,37)]. WBRT did not lead to reductions in proangiogenic factors or to increases in antiangiogenic factors in the circulation.…”

Microarray Analysis Reveals a Potential Role of lncRNA Expression in 3,4-Benzopyrene/Angiotensin II-Activated Macrophage in Abdominal Aortic Aneurysm

“…Horio et al found that endothelial cell-derived Angptl2 accelerates vascular inflammation by activating proinflammatory signaling and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression [ 29 ]. Richardson et al concluded that Angptl2 positively regulates endothelial colony-forming cell (ECFC) formation in vitro through its effects on migration and in part by activating JNK and increasing MT1-MMP expression [ 30 ]. Therefore, we hypothesize that lncRNA-Angptl2 may play a key role in the formation of AAA, through acting on its associated gene Angptl2 and inducing dysfunction of EPCs and macrophages.…”