A mechanosensitive transcriptional mechanism that controls angiogenesis.
Angiogenesis is controlled by physical interactions between cells and extracellular matrix as well as soluble angiogenic factors, such as VEGF. However, the mechanism by which mechanical signals integrate with other microenvironmental cues to regulate neovascularization remains unknown. Here we show that the Rho inhibitor, p190RhoGAP (also known as GRLF1), controls capillary network formation in vitro in human microvascular endothelial cells and retinal angiogenesis in vivo by modulating the balance of activities between two antagonistic transcription factors, TFII-I (also known as GTF2I) and GATA2, that govern gene expression of the VEGF receptor VEGFR2 (also known as KDR). Moreover, this new angiogenesis signalling pathway is sensitive to extracellular matrix elasticity as well as soluble VEGF. This is, to our knowledge, the first known functional cross-antagonism between transcription factors that controls tissue morphogenesis, and that responds to both mechanical and chemical cues.
Mammoto
Akiko
A
Vascular Biology Program, Department of Pathology & Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Connor
Kip M
KM
Mammoto
Tadanori
T
Yung
Chong Wing
CW
Huh
Dongeun
D
Aderman
Christopher M
CM
Mostoslavsky
Gustavo
G
Smith
Lois E H
LE
Ingber
Donald E
DE
D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000254:growth & development; D005109:Extracellular Matrix / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000378:metabolism; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000235:genetics* / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012171:Retinal Vessels / Q000254:growth & development / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019473:Transcription Factors, TFII / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
C074560:ARHGAP35 protein, human; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C104259:GTF2I protein, human; D020662:Guanine Nucleotide Exchange Factors; D012097:Repressor Proteins; D014157:Transcription Factors; D019473:Transcription Factors, TFII; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2