Regulation of embryonic lung vascular development by vascular endothelial growth factor receptors, Flk-1 and Flt-1.
The biological effects of vascular endothelial growth factor A (VEGF-A) are mediated by fetal liver kinase-1 (Flk-1) and fms-like tyrosine kinase-1 (Flt-1). In lung tissue, VEGF-A is diffusely expressed throughout the embryonic stages, whereas the development of vascular endothelial cells is not uniform. Noting the signaling properties of the two receptors, we hypothesized that Flk-1 and Flt-1 regulate the embryonic development of lung vasculature. We herein show the spatiotemporal expression and experimental inhibition of Flk-1 and Flt-1 of embryonic mouse lung tissue. When Flk-1 was predominantly expressed (embryonic day [E] 9.5-E13.5), then vascular endothelial cells actively proliferated. When Flt-1 was enhanced (E14.5-E16.5), these cells less actively proliferated, thereby constituting organized networks. The treatment of cultured lung buds (E11.5) with antisense oligonucleotides complementary to Flk-1 inhibited branching of capillaries and proliferation of endothelial cells. In contrast, the inhibition of Flt-1 promoted the branching of capillaries and enhanced proliferation of endothelial cells. Of interest, inhibition of Flt-1 promoted Flk-1 expression. These results suggest that the two VEGF-A receptors regulate pulmonary vascular development by modulating the VEGF-A signaling.
Yamamoto
Yasutoshi
Y
Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.
Shiraishi
Isao
I
Dai
Ping
P
Hamaoka
Kenji
K
Takamatsu
Tetsuro
T
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000196:embryology* / Q000502:physiology*; D036388:Ephrin-B2 / Q000235:genetics / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D008168:Lung / Q000098:blood supply* / Q000166:cytology / Q000196:embryology*; D051379:Mice; D008813:Mice, Inbred ICR; D009024:Morphogenesis / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000502:physiology*
D036388:Ephrin-B2; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2