dc.contributor.author | Choi, Yeong-Hoon | |
dc.contributor.author | Poutias, Dimitrios | |
dc.contributor.author | Stamm, Christof | |
dc.contributor.author | Cowan, Douglas Burr | |
dc.contributor.author | Nathan, Meena | |
dc.contributor.author | Del Nido, Pedro J. | |
dc.contributor.author | McGowan, Francis Xavier | |
dc.date.accessioned | 2011-03-19T07:01:23Z | |
dc.date.issued | 2008 | |
dc.identifier.citation | Choi, Yeong-Hoon, Douglas B. Cowan, Meena Nathan, Dimitrios Poutias, Christof Stamm, Pedro J. del Nido, and Francis X. McGowan. 2008. Myocardial hypertrophy overrides the angiogenic response to hypoxia. PLoS ONE 3(12): e4042. | en_US |
dc.identifier.issn | 1932-6203 | en_US |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:4745735 | |
dc.description.abstract | Background: Cyanosis and myocardial hypertrophy frequently occur in combination. Hypoxia or cyanosis can be potent inducers of angiogenesis, regulating the expression of hypoxia-inducible factors (HIF), vascular endothelial growth factors (VEGF), and VEGF receptors (VEGFR-1 and 2); in contrast, pressure overload hypertrophy is often associated with impaired pro-angiogenic signaling and decreased myocardial capillary density. We hypothesized that the physiological pro-angiogenic response to cyanosis in the hypertrophied myocardium is blunted through differential HIF and VEGF-associated signaling. Methods and Results: Newborn rabbits underwent aortic banding and, together with sham-operated littermates, were transferred into a hypoxic chamber (FiO2 = 0.12) at 3 weeks of age. Control banded or sham-operated rabbits were housed in normoxia. Systemic cyanosis was confirmed (hematocrit, arterial oxygen saturation, and serum erythropoietin). Myocardial tissue was assayed for low oxygen concentrations using a pimonidazole adduct. At 4 weeks of age, HIF-1α and HIF-2α protein levels, HIF-1α DNA-binding activity, and expression of VEGFR-1, VEGFR-2, and VEGF were determined in hypoxic and normoxic rabbits. At 6 weeks of age, left-ventricular capillary density was assessed by immunohistochemistry. Under normoxia, capillary density was decreased in the banded rabbits compared to non-banded littermates. As expected, non-hypertrophied hearts responded to hypoxia with increased capillary density; however, banded hypoxic rabbits demonstrated no increase in angiogenesis. This blunted pro-angiogenic response to hypoxia in the hypertrophied myocardium was associated with lower HIF-2α and VEGFR-2 levels and increased HIF-1α activity and VEGFR-1 expression. In contrast, non-hypertrophied hearts responded to hypoxia with increased HIF-2α and VEGFR-2 expression with lower VEGFR-1 expression. Conclusion: The participation of HIF-2α and VEGFR-2 appear to be required for hypoxia-stimulated myocardial angiogenesis. In infant rabbit hearts with pressure overload hypertrophy, this pro-angiogenic response to hypoxia is effectively uncoupled, apparently in part due to altered HIF-mediated signaling and VEGFR subtype expression. | en_US |
dc.language.iso | en_US | en_US |
dc.publisher | Public Library of Science | en_US |
dc.relation.isversionof | doi:10.1371/journal.pone.0004042 | en_US |
dc.relation.hasversion | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2603310/pdf/ | en_US |
dash.license | LAA | |
dc.title | Myocardial Hypertrophy Overrides the Angiogenic Response to Hypoxia | en_US |
dc.type | Journal Article | en_US |
dc.description.version | Version of Record | en_US |
dc.relation.journal | PLoS ONE | en_US |
dash.depositing.author | Cowan, Douglas Burr | |
dc.date.available | 2011-03-19T07:01:23Z | |
dash.affiliation.other | HMS^Anaesthesia-Children's Hospital | en_US |
dash.affiliation.other | HMS^Surgery-Children's Hospital | en_US |
dash.affiliation.other | HMS^Anaesthesia-Children's Hospital | en_US |
dc.identifier.doi | 10.1371/journal.pone.0004042 | * |
dash.authorsordered | false | |
dash.contributor.affiliated | McGowan, Francis | |
dash.contributor.affiliated | Nathan, Meena | |
dash.contributor.affiliated | Cowan, Douglas | |
dash.contributor.affiliated | Del Nido, Pedro | |