MODULATION OF PLATELET-DERIVED GROWTH-FACTOR RECEPTOR EXPRESSION IN MICROVASCULAR ENDOTHELIAL-CELLS DURING IN-VITRO ANGIOGENESIS

Microvascular endothelial cells in vivo exhibit a plastic phenotype, f orming a nonproliferative, differentiated capillary net-work, while re taining their ability to respond to injury by proliferation, migration and neovascularization. The presence of PDGF receptors and PDGF respo nsiveness in microvascular endothelial cells and the significance of P DGF isoforms in the control of endothelial cell growth and differentia tion remain controversial. Since culture of microvascular endothelial cells in a three-dimensional (3D) system induced cell differentiation and angiogenesis and inhibited proliferation, the present study invest igates the role of different extracellular matrix environments in indu cing different microvascular endothelial cell phenotypes on microvascu lar endothelial cell PDGF receptor expression and PDGF responsiveness. In conventional two-dimensional (2D) culture, microvascular endotheli al cells expressed both PDGF receptor alpha and beta chains. Suramin t reatment demonstrated continuous downregulation of the alpha receptor surface expression. PDGF BB and, to a lesser extent, PDGF AB were mito genic in 2D-culture, PDGF AA failed to induce any proliferative respon se despite inducing receptor autophosphorylation. During in vitro angi ogenesis induced by 3D-culture, both PDGF receptors were rapidly downr egulated. Assessment of cell proliferation showed quiescent cells and PDGF unresponsiveness. We conclude that the induction of a differentia ted phenotype during in vitro angiogenesis (tube formation) driven in part by the spatial organization of the surrounding matrix is associat ed with a downregulation of PDGF receptors. Identification of the mole cular cell-matrix interactions involved in this receptor regulation ma y allow for targeted manipulation of cell growth in vivo and lead to n ovel therapeutic applications for PDGF.