Genetic targeting of sprouting angiogenesis using Apln-CreER

Abstract

Under pathophysiological conditions in adults, endothelial cells (ECs) sprout from pre-existing blood vessels to form new ones by a process termed angiogenesis. During embryonic development, Apelin (APLN) is robustly expressed in vascular ECs. In adult mice, however, APLN expression in the vasculature is significantly reduced. Here we show that APLN expression is reactivated in adult ECs after ischaemia insults. In models of both injury ischaemia and tumor angiogenesis, we find that Apln-CreER genetically labels sprouting but not quiescent vasculature. By leveraging this specific activity, we demonstrate that abolishment of the VEGF–VEGFR2 signalling pathway as well as ablation of sprouting ECs diminished tumour vascularization and growth without compromising vascular homeostasis in other organs. Collectively, we show that Apln-CreER distinguishes sprouting vessels from stabilized vessels in multiple pathological settings. The Apln-CreER line described here will greatly aid future mechanistic studies in both vascular developmental biology and adult vascular diseases.

Endothelial Plasticity Drives Arterial Remodeling Within the Endocardium After Myocardial Infarction

“…These data are supported by results from genetic tracing using AplnCreER showing active angiogenesis taking place after MI. 22 Our data reveal active angiogenesis of endocardial endothelial cells, followed by upregulation of Cx40 expression and proliferation of subendocardial SMCs suggesting that endocardial cells are predominantly destined to an arterial phenotype.…”

Elafin Reverses Pulmonary Hypertension via Caveolin-1–Dependent Bone Morphogenetic Protein Signaling

“…Regression of vascular obliterative changes and the increase in DPA number in elafin-treated rats was associated with an elevation in whole-lung mRNA expression of apelin and its target eNOS (26). These features seem to reflect new or regenerating arteries ( Figures 2G-2I) (27).…”

Temporal Expression of Apelin/Apelin Receptor in Ischemic Stroke and its Therapeutic Potential

“…Accumulated evidence indicates that apelin/APLNR improves the recovery from ischemic stroke by inhibiting cell death and facilitating angiogenesis, which are mediated by the activation of PI3K/AKT and ERKs signaling pathways, respectively (Figure 3; Chuang et al, 2011; Tao et al, 2011; Gu et al, 2013; Wang et al, 2013; Zhu et al, 2013; Yang et al, 2014; Chen et al, 2015; Liu et al, 2015; Huang et al, 2016; Novakova et al, 2016; Zou et al, 2016). Oxidative stress is a major mechanism of ischemia/reperfusion injury, leading to cell death.…”

“…Apelin facilitates angiogenesis and blood flow restoration, which is dependent on an increase in vascular endothelial growth factor- vascular endothelial growth factor receptor 2 (VEGF-VEGFR2) signaling . In addition, PI3K/AKT and ERKs signaling pathways play a crucial role in apelin/APLNR-induced angiogenesis in ischemic stroke, which may be mediated by VEGF-VEGFR2 (Wang et al, 2013; Chen et al, 2015; Liu et al, 2015; Novakova et al, 2016). Consistently, loss of apelin impairs the angiogenesis and functional recovery (Wang et al, 2013).…”