Targeting endothelium-pericyte cross talk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis

Shuei Liong Lin, Fan Chi Chang, Claudia Schrimpf, Yi Ting Chen, Ching Fang Wu, Vin Cent Wu, Wen Chih Chiang, Frank Kuhnert, Calvin J. Kuo, Yung Ming Chen, Kwan Dun Wu, Tun Jun Tsai, Jeremy S. Duffield

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173 Citations (Scopus)

Abstract

Microvascular pericytes and perivascular fibroblasts have recently been identified as the source of scar-producing myofibroblasts that appear after injury of the kidney. We show that cross talk between pericytes and endothelial cells concomitantly dictates development of fibrosis and loss of microvasculature after injury. When either platelet-derived growth factor receptor (R)-β signaling in pericytes or vascular endothelial growth factor (VEGF)R2 signaling in endothelial cells was blocked by circulating soluble receptor ectodomains, both fibrosis and capillary rarefaction were markedly attenuated during progressive kidney injury. Blockade of either receptor-mediated signaling pathway prevented pericyte differentiation and proliferation, but VEGFR2 blockade also attenuated recruitment of inflammatory macrophages throughout disease progression. Whereas injury down-regulated angiogenic VEGF164, the dys-angiogenic isomers VEGF120 and VEGF188 were up-regulated, suggesting that pericyte-myofibroblast differentiation triggers endothelial loss by a switch in secretion of VEGF isomers. These findings link fibrogenesis inextricably with microvascular rarefaction for the first time, add new significance to fibrogenesis, and identify novel therapeutic targets.

Original languageEnglish
Pages (from-to)911-923
Number of pages13
JournalAmerican Journal of Pathology
Volume178
Issue number2
DOIs
Publication statusPublished - Feb 2011
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Lin, S. L., Chang, F. C., Schrimpf, C., Chen, Y. T., Wu, C. F., Wu, V. C., Chiang, W. C., Kuhnert, F., Kuo, C. J., Chen, Y. M., Wu, K. D., Tsai, T. J., & Duffield, J. S. (2011). Targeting endothelium-pericyte cross talk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis. American Journal of Pathology, 178(2), 911-923. https://doi.org/10.1016/j.ajpath.2010.10.012