NFATc1 mediates vascular endothelial growth factor-induced proliferation of human pulmonary valve endothelial cells.
Mice deficient for the transcription factor NFATc1 fail to form pulmonary and aortic valves, a defect reminiscent of some types of congenital human heart disease. We examined the mechanisms by which NFATc1 is activated and translocated to the nucleus in human pulmonary valve endothelial cells to gain a better understanding of its potential role(s) in post-natal valvular repair as well as valve development. Herein we demonstrate that activation of NFATc1 in human pulmonary valve endothelial cells is specific to vascular endothelial growth factor (VEGF) signaling through VEGF receptor 2. VEGF-induced NFATc1 nuclear translocation was inhibited by either cyclosporin A or a calcineurin-specific peptide inhibitor; these findings suggest that VEGF stimulates NFATc1 nuclear import in human pulmonary valve endothelial cells by a calcineurin-dependent mechanism. Importantly, both cyclosporin A and the calcineurin-specific peptide inhibitor reduced VEGF-induced human pulmonary valve endothelial cell proliferation, indicating a functional role for NFATc1 in endothelial growth. In contrast, VEGF-induced proliferation of human dermal microvascular and human umbilical vein endothelial cells was not sensitive to cyclosporin A. Finally, NFATc1 was detected in the endothelium of human pulmonary valve leaflets by immunohistochemistry. These results suggest VEGF-induced NFATc1 activation may be an important mechanism in cardiac valve maintenance and function by enhancing endothelial proliferation.
Johnson
Ehrin N
EN
Department of Surgery, Children's Hospital , Harvard Medical School, Boston, Massachusetts 02115,USA.
Lee
You Mie
YM
Sander
Tara L
TL
Rabkin
Elena
E
Schoen
Frederick J
FJ
Kaushal
Sunjay
S
Bischoff
Joyce
J
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D015153:Blotting, Western; D002455:Cell Division / Q000502:physiology*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000502:physiology*; D016228:Endothelial Growth Factors / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008222:Lymphokines / Q000502:physiology*; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011664:Pulmonary Valve / Q000166:cytology*; D014157:Transcription Factors / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors