Regulation of endothelial cell proliferation by primary monocytes

  • Schubert S
  • Benarroch A
  • Ostvang J
 et al. 
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Abstract

OBJECTIVE - Endothelial cell-monocyte cross talk is essential for vascular repair. Monocytes colocalize with endothelial cells forming a complex set of interactions distinct from the growth promoting cytokines secreted by differentiated macrophages. In the present work we examined the growth regulation and in vitro wound repair early after binding of monocytes to endothelial cells. METHODS AND RESULTS - After direct contact with primary unactivated monocytes, endothelial cells enter S-phase through a mechanism mediated in part by contact-dependent activation of endothelial Met as demonstrated by siRNA silencing of Met, neutralizing antibodies for hepatocyte growth factor and Met as well as by specific inhibition of Met by the Met kinase inhibitor SU11274. Monocytes robustly promote endothelial cell proliferation and migration into a wounded endothelial monolayer. Monocyte-induced endothelial cell proliferation is accompanied by prolonged extracellular signal-regulated kinase (ERK) activation and is inhibited by the specific ERK inhibitor PD98059. The contact-mediated effect of monocytes is specific to endothelial cells and does not occur with vascular smooth muscle cells. Interestingly, although Flk1 is activated by monocytes, the proliferative effect of monocytes reported here is minimally mediated by Flk1 signaling. CONCLUSIONS - These results suggest that the early interaction between endothelial cells and monocytes is critical for the regulation of endothelial cell proliferation. This complex regulation is mediated in part by contact-dependent Met and ERK phosphorylation. These findings add to a broader set of leukocyte-endothelial contact mediated signals that together regulate endothelial function in health and disease. © 2008 American Heart Association, Inc.

Author-supplied keywords

  • Angiogenesis
  • Endothelial cell proliferation
  • Endothelium
  • Monocytes
  • Vascular remodeling

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Authors

  • S.Y. Schubert

  • A. Benarroch

  • J. Ostvang

  • E.R. Edelman

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