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We have used primary human and rat long bone\u2010derived osteoblast\u2010like cells (HOB and LOB) and human umbilical vein endothelial cells (HUVEC) to interrogate the potential autocrine\/paracrine role of vascular endothelial cell growth factor (VEGF) in osteoblast:endothelial cell (OB:EC) communication and examined whether prostaglandins (PG), known modulators of both OB and EC behavior, modify VEGF production. We found that the stable metabolite of PGI<jats:sub>2<\/jats:sub>, 6\u2010keto\u2010PGF<jats:sub>1\u03b1<\/jats:sub> and PGE<jats:sub>2<\/jats:sub>, induced a concentration\u2010dependent increase in VEGF release by HOBs but not ECs. In ECs, VEGF promoted early ERK1\/2 activation, late cyclooxygenase\u20102 (COX\u20102) protein induction, and release of 6\u2010keto\u2010PGF<jats:sub>1\u03b1<\/jats:sub>. In marked contrast, no significant modulation of these events was observed in HOBs exposed to VEGF, but LOBs clearly exhibited COX\u2010dependent prostanoid release (10\u2010fold less than EC) following VEGF treatment. A low level of osteoblast\u2010like cell responsiveness to exogenous VEGF was supported by VEGFR2\/Flk\u20101 immunolabelling and by blockade of VEGF\u2010mediated prostanoid generation by a VEGFR tyrosine kinase inhibitor (TKI). HOB alkaline phosphatase (ALP) activity was increased following long\u2010term non\u2010contact co\u2010culture with ECs and exposure of ECs to VEGF in this system further increased OB\u2010like cell differentiation and markedly enhanced prostanoid release. Our studies confirm a paracrine EC\u2010mediated effect of VEGF on OB\u2010like cell behavior and are the first supporting a model in which prostanoids may facilitate this unidirectional VEGF\u2010driven OB:EC communication. These findings may offer novel regimes for modulating pathological bone remodeling anomalies through the control of the closely coupled vascular supply. J. Cell. Physiol. 214: 537\u2013544, 2008. \u00a9 2007 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcp.21234","type":"journal-article","created":{"date-parts":[[2007,8,8]],"date-time":"2007-08-08T17:19:29Z","timestamp":1186593569000},"page":"537-544","source":"Crossref","is-referenced-by-count":122,"title":["Evaluation of VEGF\u2010mediated signaling in primary human cells reveals a paracrine action for VEGF in osteoblast\u2010mediated crosstalk to endothelial cells"],"prefix":"10.1002","volume":"214","author":[{"given":"Claire E.","family":"Clarkin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger J.","family":"Emery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew A.","family":"Pitsillides","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline 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