Faculty Collaboration Database

Endothelial TWIST1 promotes pathological ocular angiogenesis. Invest Ophthalmol Vis Sci 2014 Nov 20;55(12):8267-77

Date

11/22/2014

Pubmed ID

25414194

Pubmed Central ID

PMC4541480

DOI

10.1167/iovs.14-15623

Scopus ID

2-s2.0-84919360479 (requires institutional sign-in at Scopus site)   41 Citations

Abstract

PURPOSE: Pathological neovessel formation impacts many blinding vascular eye diseases. Identification of molecular signatures distinguishing pathological neovascularization from normal quiescent vessels is critical for developing new interventions. Twist-related protein 1 (TWIST1) is a transcription factor important in tumor and pulmonary angiogenesis. This study investigated the potential role of TWIST1 in modulating pathological ocular angiogenesis in mice.

METHODS: Twist1 expression and localization were analyzed in a mouse model of oxygen-induced retinopathy (OIR). Pathological ocular angiogenesis in Tie2-driven conditional Twist1 knockout mice were evaluated in both OIR and laser-induced choroidal neovascularization models. In addition, the effects of TWIST1 on angiogenesis and endothelial cell function were analyzed in sprouting assays of aortic rings and choroidal explants isolated from Twist1 knockout mice, and in human retinal microvascular endothelial cells treated with TWIST1 small interfering RNA (siRNA).

RESULTS: TWIST1 is highly enriched in pathological neovessels in OIR retinas. Conditional Tie2-driven depletion of Twist1 significantly suppressed pathological neovessels in OIR without impacting developmental retinal angiogenesis. In a laser-induced choroidal neovascularization model, Twist1 deficiency also resulted in significantly smaller lesions with decreased vascular leakage. In addition, loss of Twist1 significantly decreased vascular sprouting in both aortic ring and choroid explants. Knockdown of TWIST1 in endothelial cells led to dampened expression of vascular endothelial growth factor receptor 2 (VEGFR2) and decreased endothelial cell proliferation.

CONCLUSIONS: Our study suggests that TWIST1 is a novel regulator of pathologic ocular angiogenesis and may represent a new molecular target for developing potential therapeutic treatments to suppress pathological neovascularization in vascular eye diseases.

Author List

Li J, Liu CH, Sun Y, Gong Y, Fu Z, Evans LP, Tian KT, Juan AM, Hurst CG, Mammoto A, Chen J

Author

Akiko Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Choroid
Choroidal Neovascularization
Disease Models, Animal
Endothelial Cells
Fluorescein Angiography
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Microvessels
Neovascularization, Pathologic
Nuclear Proteins
Oxygen
RNA, Messenger
Retinal Neovascularization
Retinal Vessels
Twist-Related Protein 1
Vascular Endothelial Growth Factor Receptor-2