Delineating the angiogenic gene expression profile before pulmonary vascular remodeling in a lamb model of congenital heart disease.

Tian, J; Fratz, S; Hou, Y; Lu, Q; Gorlach, A; Hess, J; Schreiber, C; Datar, SA; Oishi, PE; Nechtman, J; Podolsky, R; She, JX; Fineman, JR; Black, SM

doi:10.1152/physiolgenomics.00135.2010

journal article

Title:: Delineating the angiogenic gene expression profile before pulmonary vascular remodeling in a lamb model of congenital heart disease.
Document type:: Journal Article; Article
Author(s):: Tian, J; Fratz, S; Hou, Y; Lu, Q; Gorlach, A; Hess, J; Schreiber, C; Datar, SA; Oishi, PE; Nechtman, J; Podolsky, R; She, JX; Fineman, JR; Black, SM
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.
Journal title abbreviation:: Physiol Genomics
Year:: 2011
Journal volume:: 43
Journal issue:: 2
Pages contribution:: 87-98
Language:: eng
Fulltext / DOI:: doi:10.1152/physiolgenomics.00135.2010
Pubmed ID:: http://view.ncbi.nlm.nih.gov/pubmed/20978110
Print-ISSN:: 1094-8341
TUM Institution:: Klinik für Herz- und Gefäßchirurgie (Prof. Lange); Klinik für Kinderkardiologie und angeborene Herzfehler (Prof. Hess)
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Occurrences:

mediaTUM Gesamtbestand Einrichtungen Schools TUM School of Medicine and Health Departments Clinical Medicine Lehr- und Forschungskooperationen mit den Kliniken und Instituten am Deutschen Herzzentrum Klinik für Kinderkardiologie und angeborene Herzfehler (DHM) (Prof. Ewert)2011

mediaTUM Gesamtbestand Einrichtungen Schools TUM School of Medicine and Health Departments Clinical Medicine Lehr- und Forschungskooperationen mit den Kliniken und Instituten am Deutschen Herzzentrum Klinik für Herz- und Gefäßchirurgie (DHM) (Prof. Krane)2011