Angiopoietin-4-dependent venous maturation and fluid drainage in the peripheral retina

Abstract

The maintenance of fluid homeostasis is necessary for function of the neural retina; however, little is known about the significance of potential fluid management mechanisms. Here, we investigated angiopoietin-4 (Angpt4, also known as Ang3), a poorly characterized ligand for endothelial receptor tyrosine kinase Tie2, in mouse retina model. By using genetic reporter, fate mapping, and in situ hybridization, we found Angpt4 expression in a specific sub-population of astrocytes at the site where venous morphogenesis occurs and that lower oxygen tension, which distinguishes peripheral and venous locations, enhances Angpt4 expression. Correlating with its spatiotemporal expression, deletion of Angpt4 resulted in defective venous development causing impaired venous drainage and defects in neuronal cells. In vitro characterization of angiopoietin-4 proteins revealed both ligand-specific and redundant functions among the angiopoietins. Our study identifies Angpt4 as the first growth factor for venous-specific development and its importance in venous remodeling, retinal fluid clearance and neuronal function.

Caveolae-mediated Tie2 signaling contributes to CCM pathogenesis in a brain endothelial cell-specific Pdcd10-deficient mouse model

“…It is still unknown why CCM lesions progress more rapidly in cerebellum compared to cerebrum. This could be related to the unique structure and hemodynamics of cerebellum 13,36 or spatial expression of the Angpt-Tie2 signaling as reported previously 37,38 . CCM lesions in Pdcd10 BECKO mice were not only detected in the cerebellum but also in the cerebrum, allowing us to perform experiments visualizing the vascular dynamics of CCM lesions using transcranial two-photon microscopy.…”

PHD2 deletion in endothelial or arterial smooth muscle cells reveals vascular cell type-specific responses in pulmonary hypertension and fibrosis

“…To confirm the efficiency and cell type specificity of the Cre/loxP recombination Chd5 CreERT2 ; Rosa26 mTmG Cre-reporter mice [67] were treated with the same tamoxifen dosage as above and GFP expression was investigated by confocal microscopy as an indication for Cre/ loxP mediated recombination from tissues of 10-month-old mice. To achieve aSMCs specific Phd2 deletion in the lungs, a floxed Phd2 allele was crossed with an Angpt4 Cre mouse line [34] to generate Phd2 ΔaSMC (Angpt4 Cre/+ ; Phd2 loxP/loxP ). To confirm efficiency and cell type specificity of the Cre/ loxP recombination Angpt4 Cre were crossed with Rosa-26 mTmG mice.…”

“…To study the role of PHD2 in aSMCs in vivo we utilized a novel Angpt4 Cre knock-in allele. In our previous work we found Angpt4 expression in aSMCs of the small intestine mesentery in adult mice [34]. To characterize the spatiotemporal expression pattern of Angpt4 in more detail, Angpt4 mRNA expression was investigated by qPCR and its cellular source analyzed in the fate mapping Angpt4 Cre ; Rosa26 mT/mG mice.…”

Lymphatics in Eye Fluid Homeostasis: Minor Contributors or Significant Actors?

“…A compensatory effect between both ligands has been evidenced by the lack of lymphatic defects if only single conditional deletion of either angiopoietin-1 or angiopoietin-2 alone was performed [51]. In the future, it may be interesting to check if angiopoietin-4, another identified ligand for endothelial receptor tyrosine kinase TIE-2, which appear involved in venous development [52], may participate in the process.…”