The matricellular protein CCN1 controls retinal angiogenesis by targeting VEGF, Src homology 2 domain phosphatase-1 and Notch signaling

Hemabindu Chintala, Izabela Krupska, Lulu Yan, Lester Lau, Maria Grant, Brahim Chaqour

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Physiological angiogenesis depends on the highly coordinated actions of multiple angiogenic regulators. CCN1 is a secreted cysteine-rich and integrin-binding matricellular protein required for proper cardiovascular development. However, our understanding of the cellular origins and activities of this molecule is incomplete. Here, we show that CCN1 is predominantly expressed in angiogenic endothelial cells (ECs) at the leading front of actively growing vessels in themouse retina. Endothelial deletion of CCN1 in mice using a Cre-Lox system is associated with EC hyperplasia, loss of pericyte coverage and formation of dense retinal vascular networks lacking the normal hierarchical arrangement of arterioles, capillaries and venules. CCN1 is a product of an immediateearly gene that is transcriptionally induced in ECs in response to stimulation by vascular endothelial growth factor (VEGF).We found that CCN1 activity is integrated with VEGF receptor 2 (VEGF-R2) activation and downstream signaling pathways required for tubular network formation. CCN1-integrin binding increased the expression of and association between Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1) and VEGF-R2, which leads to rapid dephosphorylation of VEGF-R2 tyrosine, thus preventing EC hyperproliferation. Predictably, CCN1 further brings receptors/signaling molecules into proximity that are otherwise spatially separated. Furthermore, CCN1 induces integrin-dependent Notch activation in cultured ECs, and its targeted gene inactivation in vivo alters Notchdependent vascular specification and remodeling, suggesting that functional levels of Notch signaling requires CCN1 activity. These data highlight novel functions ofCCN1as a naturally optimizedmolecule, fine-controlling key processes in physiological angiogenesis and safeguarding against aberrant angiogenic responses.

Original languageEnglish (US)
Pages (from-to)2364-2374
Number of pages11
JournalDevelopment (Cambridge)
Volume142
Issue number13
DOIs
StatePublished - Jul 1 2015

Keywords

  • CCN1
  • Knockout mouse
  • Matricellular
  • Retinal angiogenesis
  • VEGF

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology

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