The transcription factor MEF2C-null mouse exhibits complex vascular malformations and reduced cardiac expression of angiopoietin 1 and VEGF.
The MEF2 family of transcription factors has been implicated in transcriptional regulation in a number of different cell types. Targeted deletion of the MEF2C gene, in particular, revealed its importance for early cardiogenesis (Q. Lin et al., 1997, Science 276, 1404-1407). We report here that this deletion also resulted in vascular anomalies characterized by extreme variability in lumen size and defects in remodeling. While primary vascular networks formed in the yolk sac of the mutants, they failed to remodel into more complex vascular structures. Likewise, although the primordia of the dorsal aortae formed normally, anomalies were observed in these vessels later in development. Dorsal and anterior to the heart, the aortae exhibited abnormally small lumens, as did the anterior cardinal veins and intersegmental arteries. In contrast, the dorsal aortae and intersegmental arteries caudal to the heart were grossly enlarged. Cranial vessels were also enlarged and less branched than normal. Endocardiogenesis in the mutant was abnormal with the endothelial cells exhibiting a number of aberrant phenotypes. These endocardial defects were accompanied by a notable reduction in angiopoietin 1 and VEGF mRNA production by the myocardium, indicating that MEF2C is required for myocardial expression of these important endothelial-directed cytokines and thus for correct endocardial morphogenesis.
Bi
W
W
Division of Cardiology, University of Texas Medical School at Houston, Houston, Texas, 77030, USA.
Drake
C J
CJ
Schwarz
J J
JJ
D042683:Angiopoietin-1; D000818:Animals; D001165:Arteriovenous Malformations / Q000235:genetics*; D001808:Blood Vessels / Q000196:embryology / Q000502:physiology; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology / Q000502:physiology*; D008222:Lymphokines / Q000096:biosynthesis*; D064326:MEF2 Transcription Factors; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D018006:Myogenic Regulatory Factors / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D016228:Endothelial Growth Factors; D008222:Lymphokines; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D008562:Membrane Glycoproteins; D018006:Myogenic Regulatory Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors