Angiopoietin-1 is essential in mouse vasculature during development and in response to injury

Abstract

Angiopoietin-1/Tek signaling is a critical regulator of blood vessel development, with conventional knockout of angiopoietin-1 or Tek in mice being embryonically lethal due to vascular defects. In addition, angiopoietin-1 is thought to be required for the stability of mature vessels. Using a Cre-Lox conditional gene targeting approach, we have studied the role of angiopoietin-1 in embryonic and adult vasculature. We report here that angiopoietin-1 is critical for regulating both the number and diameter of developing vessels but is not required for pericyte recruitment. Cardiac-specific knockout of angiopoietin-1 reproduced the phenotype of the conventional knockout, demonstrating that the early vascular abnormalities arise from flow-dependent defects. Strikingly, deletion in the entire embryo after day E13.5 produced no immediate vascular phenotype. However, when combined with injury or microvascular stress, angiopoietin-1 deficiency resulted in profound organ damage, accelerated angiogenesis, and fibrosis. These findings redefine our understanding of the biological roles of angiopoietin-1: it is dispensable in quiescent vessels but has a powerful ability to modulate the vascular response after injury.

Lung Pericytes and Resident Fibroblasts

“…3,5,18,46 Unlike the PDGF pathway, disconnecting Ang-1 from Tie-2 does not interfere with pericyte positioning or reduce their vascular coverage, although it does alter the number and proportions of vessels during embryonic development. 3,5,43 Instead, targeted Ang-1 deficiency exacerbated fibrosis in response to physical damage or vascular stress, implying that the Ang-1/Tie2 connection between pericytes and endothelial cells regulates their coordinated response to injury. 3,43 Figure 3 Collagen (Col) 1 expression distinguishes between immune and matrix-oriented lung fibroblasts.…”

“…3,5,43 Instead, targeted Ang-1 deficiency exacerbated fibrosis in response to physical damage or vascular stress, implying that the Ang-1/Tie2 connection between pericytes and endothelial cells regulates their coordinated response to injury. 3,43 Figure 3 Collagen (Col) 1 expression distinguishes between immune and matrix-oriented lung fibroblasts. Hung et al 10 characterized the most enriched Kyoto Encyclopaedia of Genes and Genomes gene ontology pathways (www.…”

Reduced Krüppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy

“…The alteration of expression of these genes is known to be associated with CKD, such as diabetic nephropathy. 36 Although the exact mechanisms and consequences of these gene expression changes remain to be determined, it suggests that KLF2 may be up-regulated by glomerular hyperfiltrationeinduced shear stress and protect against endothelial cell injury through direct and indirect transcriptional regulation of several key endothelial cell markers.…”

Pdgfrb‐Cre targets lymphatic endothelial cells of both venous and non‐venous origins

“…The Pdgfrb‐Cre line (Foo et al ., 2006), where Cre recombinase expression is driven by a transgenic fragment of the gene for platelet‐derived growth factor receptor β ( Pdgfrb ), has been used extensively to specifically target mural cells, namely vascular smooth muscle cells, pericytes and hepatic stellate cells; examples are given in ref (Abraham et al ., 2008; Foo et al ., 2006; Greif et al ., 2012; Henderson et al ., 2013; Jeansson et al ., 2011; Kogata et al ., 2009; Siegenthaler et al ., 2013; Stenzel et al ., 2009; Ye et al ., 2009; You et al ., 2014). We (Stanczuk et al ., 2015) and others (Klotz et al ., 2015) recently showed that Pdgfrb‐Cre unexpectedly also targets a large proportion of embryonic lymphatic endothelial cells (LECs) in the developing mesentery (Stanczuk et al ., 2015) and the heart (Klotz et al ., 2015).…”