Activation of the endothelin system mediates pathological angiogenesis during ischemic retinopathy

Chintan Patel, S. Priya Narayanan, Wenbo Zhang, Zhimin Xu, Sangeetha Sukumari-Ramesh, Krishnan M. Dhandapani, R. William Caldwell, Ruth B. Caldwell

Research output: Contribution to journalArticle

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Abstract

Retinopathy of prematurity adversely affects premature infants because of oxygen-induced damage of the immature retinal vasculature, resulting in pathological neovascularization (NV). Our pilot studies using the mouse model of oxygen-induced retinopathy (OIR) showed marked increases in angiogenic mediators, including endothelins and endothelin receptor (EDNR) A. We hypothesized that activation of the endothelin system via EDNRA plays a causal role in pathological angiogenesis and up-regulation of angiogenic mediators, including vascular endothelial growth factor A (VEGFA) in OIR. Mice were exposed to 75% oxygen from post-natal day P7 to P12, treated with either vehicle or EDNRA antagonist BQ-123 or EDNRB antagonist BQ-788 on P12, and kept at room air from P12 to P17 (ischemic phase). RT-PCR analysis revealed increased levels of EDN2 and EDNRA mRNA, and Western blot analysis revealed increased EDN2 expression during the ischemic phase. EDNRA inhibition significantly increased vessel sprouting, resulting in enhanced physiological angiogenesis and decreased pathological NV, whereas EDNRB inhibition modestly improved vascular repair. OIR triggered significant increases in VEGFA protein and mRNA for delta-like ligand 4, apelin, angiopoietin-2, and monocyte chemoattractant protein-1. BQ-123 treatment significantly reduced these alterations. EDN2 expression was localized to retinal glia and pathological NV tufts of the OIR retinas. EDN2 also induced VEGFA protein expression in cultured astrocytes. In conclusion, inhibition of the EDNRA during OIR suppresses pathological NV and promotes physiological angiogenesis.

Original languageEnglish (US)
Pages (from-to)3040-3051
Number of pages12
JournalAmerican Journal of Pathology
Volume184
Issue number11
DOIs
StatePublished - Nov 1 2014

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Pathologic Neovascularization
Endothelins
Oxygen
Physiologic Neovascularization
Vascular Endothelial Growth Factor A
Angiopoietin-2
Retinal Neovascularization
Endothelin A Receptors
Retinopathy of Prematurity
Messenger RNA
Chemokine CCL2
Premature Infants
Neuroglia
Astrocytes
Blood Vessels
Retina
Proteins
Up-Regulation
Western Blotting
Air

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Patel, C., Narayanan, S. P., Zhang, W., Xu, Z., Sukumari-Ramesh, S., Dhandapani, K. M., ... Caldwell, R. B. (2014). Activation of the endothelin system mediates pathological angiogenesis during ischemic retinopathy. American Journal of Pathology, 184(11), 3040-3051. https://doi.org/10.1016/j.ajpath.2014.07.012

Activation of the endothelin system mediates pathological angiogenesis during ischemic retinopathy. / Patel, Chintan; Narayanan, S. Priya; Zhang, Wenbo; Xu, Zhimin; Sukumari-Ramesh, Sangeetha; Dhandapani, Krishnan M.; Caldwell, R. William; Caldwell, Ruth B.

In: American Journal of Pathology, Vol. 184, No. 11, 01.11.2014, p. 3040-3051.

Research output: Contribution to journalArticle

Patel, C, Narayanan, SP, Zhang, W, Xu, Z, Sukumari-Ramesh, S, Dhandapani, KM, Caldwell, RW & Caldwell, RB 2014, 'Activation of the endothelin system mediates pathological angiogenesis during ischemic retinopathy', American Journal of Pathology, vol. 184, no. 11, pp. 3040-3051. https://doi.org/10.1016/j.ajpath.2014.07.012
Patel, Chintan ; Narayanan, S. Priya ; Zhang, Wenbo ; Xu, Zhimin ; Sukumari-Ramesh, Sangeetha ; Dhandapani, Krishnan M. ; Caldwell, R. William ; Caldwell, Ruth B. / Activation of the endothelin system mediates pathological angiogenesis during ischemic retinopathy. In: American Journal of Pathology. 2014 ; Vol. 184, No. 11. pp. 3040-3051.
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AU - Caldwell, Ruth B.

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