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Transforming growth factor beta signaling in hypertensive remodeling of porcine aorta

ABSTRACT: A porcine aortic coarctation model was used to examine regulation of gene expression in early hypertensive vascular remodeling. Aortic segments were collected proximal (high pressure) and distal (low pressure) to the coarctation after 2 weeks of sustained hypertension (mean arterial pressure>150mmHg). Porcine 10K oligoarrays used for gene expression profiling of the two regions of aorta revealed downregulation of cytoskeletal and upregulation of extracellular region genes relative to the whole genome. A genomic database search for transforming growth factor-β (TGFβ) control elements (TCE) showed that 19% of the genes that changed expression due to hypertension contained putative TCEs. Real time PCR and microarray analysis showed no change in expression of TGFβ1, TGFβ2, TGFβ3, or bone morphogenetc proteins (BMP)2 and 4, yet immunohistochemical staining for phosphorylated SMAD2, an indicator of TGFβ signaling, and for phosphorylated SMAD1/5/8, an indicator of signaling through the BMPs, showed the highest percentage of positively stained cells in the proximal aortic segments of occluded animals. For TGFβ signaling, this increase was significantly different from sham-operated controls. Western blot analysis showed no difference in total TGFβ1 protein levels with respect to treatment or aortic segment. Immunohistochemistry showed that the protein levels of latency associated peptide, was decreased in proximal segments of occluded animals. Collectively, these results suggest that activation of TGFβ, but not altered expression, may be a major mechanism regulating early hypertensive vascular remodeling.

ORGANISM(S): Sus scrofa

PROVIDER: GSE7115 | GEO | 2009/08/10

SECONDARY ACCESSION(S): PRJNA98423

REPOSITORIES: GEO

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Project description:Multiple molecular and cellular mechanisms are associated with the initiation and progression of aortic valve disease. Alterations in ECM remodeling, increased expression of pro-inflammatory cytokines, calcification, lipid deposition and changes in valve cell phenotype have demonstrated roles in development of aortic valve disease. Mechanical stimulation has a significant role in determining the physiological properties of valve tissue and an altered hemodynamic environment may result in pathological changes. We used microarrays to detail the global of gene expression profiles underlying valve remodeling during valve exposure to of two levels of cyclic mechanical pressure (normotensive 0-80mmHg and hypertensive 0-120mmHg ) on porcine valve tissue transcriptome using Sus Scrofa cDNA microarrays from Affymetrix and we identified distinct classes of up-regulated genes during this process. Hybridizations were carried out with RNA isolated from six independetn samples of valve tissue exposed to normotensive and hypertensive pressure for 24 hours at 1hz frecuency. Differentially expressed genes were identified by The t test with the option of unequal variance was used to calculate P values for each gene. The fold change and Q values for each gene were calculated with SAM program with permutation of 500 . Biological modeling of the differentially expressed genes (DE) was carried out based on GO groups and network analysis in ingenuity Pathway Analysis (IPA). Experiment Overall Design: The experimental design included three biological samples of porcine valve leaflets exposed to cyclic pressures of 0-80 or 0-120 mmHg for 24 hours, representing normotensive and hypertensive diastolic transvalvular pressure, respectively. Using Affymetrix porcine microarrays, we compared global gene expression profiles of aortic valve leaflets exposed to elevated and normal physiological pressure conditions . The effects of cyclic pressure on the transcriptome was determined by comparing the quantity and magnitud of change in gene expression levels of valve leflets, as well evaluating the molecular function each gene has in the cell,in the presence of hypertennsive (experimental) and normotensve pressurec (control).

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Transforming growth factor beta signaling in hypertensive remodeling of porcine aorta

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