scholarly journals Platelet-Derived Growth Factor Receptors Direct Vascular Development Independent of Vascular Smooth Muscle Cell Function

2008 ◽  
Vol 28 (18) ◽  
pp. 5646-5657 ◽  
Author(s):  
Wendy J. French ◽  
Esther E. Creemers ◽  
Michelle D. Tallquist
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Blood Vessel ◽  
Vascular Smooth Muscle ◽  
Yolk Sac ◽  
Embryonic Lethality ◽  
Platelet Derived Growth Factor ◽  
Pdgf Receptor ◽  
Cardiovascular Development ◽  
Receptor Signaling

ABSTRACT Complete loss of platelet-derived growth factor (PDGF) receptor signaling results in embryonic lethality around embryonic day 9.5, but the cause of this lethality has not been identified. Because cardiovascular failure often results in embryonic lethality at this time point, we hypothesized that a failure in cardiovascular development could be the cause. To assess the combined role of PDGF receptor α (PDGFRα) and PDGFRβ, we generated embryos that lacked these receptors in cardiomyocytes and vascular smooth muscle cells (VSMC) using conditional gene ablation. Deletion of either PDGFRα or PDGFRβ caused no overt vascular defects, but loss of both receptors using an SM22α-Cre transgenic mouse line led to a disruption in yolk sac blood vessel development. The cell population responsible for this vascular defect was the yolk sac mesothelial cells, not the cardiomyocytes or the VSMC. Coincident with loss of PDGF receptor signaling, we found a reduction in collagen deposition and an increase in MMP-2 activity. Finally, in vitro allantois cultures demonstrated a requirement for PDGF signaling in vessel growth. Together, these data demonstrate that PDGF receptors cooperate in the yolk sac mesothelium to direct blood vessel maturation and suggest that these effects are independent of their role in VSMC development.

scholarly journals Interaction of platelet-derived growth factor with thrombospondin 1

1997 ◽  
Vol 326 (3) ◽  
pp. 709-716 ◽  
Author(s):  
Philip J. HOGG ◽  
Kylie A. HOTCHKISS ◽  
Barbara M. JIMÉNEZ ◽  
Paul STATHAKIS ◽  
Colin N. CHESTERMAN
Keyword(s):  
Smooth Muscle ◽  
Ionic Strength ◽  
Growth Factor ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Dissociation Constant ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Platelet Derived Growth Factor ◽  
Pdgf Receptor

Key factors that mediate vascular smooth muscle cell proliferation and migration are platelet-derived growth factor (PDGF) and thrombospondin 1 (TSP1). We now report that PDGFBB bound tightly and specifically to TSP1, that this interaction was markedly dependent on the disulphide bond arrangement in TSP1, and that binding of PDGFBB to TSP1 did not preclude PDGFBB from binding to its receptor on rat aortic vascular smooth-muscle cells. At physiological ionic strength and pH, PDGFBB bound to Ca2+-depleted TSP1 with a dissociation constant of 11±2 nM and to Ca2+-replete TSP1 with a dissociation constant of 32±5 nM. Binding was specific, as both soluble TSP1 and unlabelled PDGFBB competed for binding of iodinated PDGFBB to immobilized TSP1, whereas other platelet α-granule proteins did not compete. The tertiary structure of TSP1 is regulated by intramolecular disulphide interchange; we found that catalysis of disulphide interchange in TSP1 by protein disulphide isomerase ablated the binding of PDGFBB. The interaction of PDGFBB with TSP1 was weakened by increasing salt concentration and essentially ablated at 0.65 ionic strength; it was inhibited by heparin with a half-maximal effect at 20 i.u./ml, implying that the binding was mediated largely by ionic interactions. An anti TSP1 monoclonal antibody decreased the binding of iodinated PDGFBB to PDGF receptor on rat aortic vascular smooth-muscle cells by 37±2%, whereas platelet TSP1 non-competitively inhibited binding of iodinated PDGFBB. Uncomplexed PDGFBB bound to PDGF receptor with an affinity 5±2 times that of PDGFBB–TSP1 complexes. These results suggest that TSP1 might assist in the targeting of PDGF to its receptor on vascular smooth-muscle cells.

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