Enhanced proangiogenic signaling in thrombospondin-1-deficient retinal endothelial cells

Microvascular Research
Yongji WangN Sheibani

Abstract

Thrombospondin-1 (TSP1) is an endogenous inhibitor of angiogenesis, which limits blood vessel density in normal tissues and curtails tumor growth. Previous studies of the molecular and cellular effects of TSP1 in angiogenesis have been contradictory. Here, we show that retinal endothelial cells (REC) prepared from TSP1-deficient (TSP1-/-) mice are more proliferative and migratory compared to the wild type REC. We observed up-regulation of the cell cycle regulators, including cyclin A, D1, and Cdk2, as well as the enhanced sequential activities of Src, PI3-kinase, Akt/PKB, Rac1/Cdc42 GTPases, and p38 MAP kinase in TSP1-/- REC. The increased levels of fibronectin and active Akt/PKB were also observed in retinal vasculature of TSP1-/- mice in vivo. Inhibition of Src/PI3-kinase/P38 MAP kinase activities in TSP1-/- REC resulted in decreased migration. Furthermore, TSP1-/- REC showed decreased intracellular levels of active Fyn and JNK2 without affecting caspase-3 activity. Thus, our results demonstrate that in the absence of TSP1, the proangiogenic signaling is enhanced, possibly through up-regulation of fibronectin expression. The enhanced signaling further promotes EC proliferation, migration, and survival. These novel observation...Continue Reading

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Citations

May 29, 2012·Current Diabetes Reports·Shuang WangElia J Duh
May 4, 2012·Cold Spring Harbor Perspectives in Medicine·Patrick R Lawler, Jack Lawler
Aug 31, 2011·Cold Spring Harbor Perspectives in Biology·Josephine C Adams, Jack Lawler
Sep 3, 2010·American Journal of Physiology. Cell Physiology·SunYoung ParkNader Sheibani
Oct 24, 2008·American Journal of Physiology. Cell Physiology·Qiong Huang, Nader Sheibani
Feb 6, 2009·American Journal of Physiology. Cell Physiology·Elizabeth A ScheefNader Sheibani
Oct 10, 2013·International Journal of Inflammation·Atul JainColin Smith
Oct 24, 2007·Life Sciences·Subir Kumar Das, D M Vasudevan
Nov 23, 2011·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Hiromitsu HayashiTakao Sakai
Jul 28, 2017·American Journal of Physiology. Cell Physiology·Juliana Falero-PerezNader Sheibani
Aug 30, 2017·Journal of Ophthalmology·A F MoleiroA Rocha-Sousa
Jul 7, 2017·Clinical Science·Mitra FarnoodianNader Sheibani
May 11, 2021·Frontiers in Cell and Developmental Biology·Christine M SorensonNader Sheibani
Nov 2, 2021·Frontiers in Cell and Developmental Biology·Christine M SorensonNader Sheibani

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