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Delineating the angiogenic gene expression profile before pulmonary vascular remodeling in a lamb model of congenital heart disease.
- Source :
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Physiological genomics [Physiol Genomics] 2011 Jan 01; Vol. 43 (2), pp. 87-98. Date of Electronic Publication: 2010 Oct 26. - Publication Year :
- 2011
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Abstract
- Disordered angiogenesis is implicated in pulmonary vascular remodeling secondary to congenital heart diseases (CHD). However, the underlying genes are not well delineated. We showed previously that an ovine model of CHD with increased pulmonary blood flow (PBF, Shunt) has an "angiogenesis burst" between 1 and 4 wk of age. Thus we hypothesized that the increased PBF elicited a proangiogenic gene expression profile before onset of vessel growth. To test this we utilized microarray analysis to identify genes that could be responsible for the angiogenic response. Total RNA was isolated from lungs of Shunt and control lambs at 3 days of age and hybridized to Affymetrix gene chips for microarray analyses (n = 8/group). Eighty-nine angiogenesis-related genes were found to be upregulated and 26 angiogenesis-related genes downregulated in Shunt compared with control lungs (cutting at 1.2-fold difference, P < 0.05). We then confirmed upregulation of proangiogenic genes FGF2, Angiopoietin2 (Angpt2), and Birc5 at mRNA and protein levels and upregulation of ccl2 at mRNA level in 3-day Shunt lungs. Furthermore, we found that pulmonary arterial endothelial cells (PAEC) isolated from fetal lambs exhibited increased expression of FGF2, Angpt2, Birc5, and ccl2 and enhanced angiogenesis when exposed to elevated shear stress (35 dyn/cm²) compared with cells exposed to more physiological shear stress (20 dyn/cm²). Finally, we demonstrated that blocking FGF2, Angpt2, Birc5, or ccl2 signaling with neutralizing antibodies or small interfering RNA (siRNA) significantly decreased the angiogenic response induced by shear stress. In conclusion, we have identified a "proangiogenic" gene expression profile in a lamb model of CHD with increased PBF that precedes onset of pulmonary vascular remodeling. Our data indicate that FGF2, Angpt2, Birc5, and ccl2 may play important roles in the angiogenic response.
- Subjects :
- Angiopoietin-2 genetics
Angiopoietin-2 metabolism
Animals
Blotting, Western
Chemokine CCL2 genetics
Chemokine CCL2 metabolism
Disease Models, Animal
Down-Regulation genetics
Endothelial Cells metabolism
Fibroblast Growth Factor 2 genetics
Fibroblast Growth Factor 2 metabolism
Heart Diseases pathology
Heart Diseases physiopathology
Hemodynamics physiology
Microtubule-Associated Proteins genetics
Microtubule-Associated Proteins metabolism
Phenotype
Pulmonary Artery pathology
RNA, Messenger genetics
RNA, Messenger metabolism
Reproducibility of Results
Reverse Transcriptase Polymerase Chain Reaction
Sheep
Stress, Mechanical
Up-Regulation genetics
Gene Expression Profiling
Heart Diseases congenital
Heart Diseases genetics
Lung blood supply
Lung physiopathology
Neovascularization, Physiologic genetics
Pulmonary Circulation genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1531-2267
- Volume :
- 43
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Physiological genomics
- Publication Type :
- Academic Journal
- Accession number :
- 20978110
- Full Text :
- https://doi.org/10.1152/physiolgenomics.00135.2010