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

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.

ACKNOWLEDGMENTS

We thank Ondine Cleaver, Dan Garry, and Eric Olson for providing the Tie2Cre^Tg, Tie2GFP^Tg, and myocardin^Cre mice, respectively. We also thank Robert Gerard for generously providing Cre-expressing adenovirus. We thank Rhonda Bassel-Duby, Rolf Brekken, Ondine Cleaver, Rita Perlingiero, and our laboratory colleagues for comments on the manuscript. We also thank Angie Bookout, Michelle Kazi, Haley Newton, Banu Eskiocak, and Holly Mead for excellent technical assistance.

We declare no competing financial interest.