Transforming growth factor-beta signaling in hypertensive remodeling of porcine aorta.
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 wk of sustained hypertension (mean arterial pressure>150 mmHg). 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-beta (TGF-beta) control elements showed that 19% of the genes that changed expression due to hypertension contained putative TGF-beta control elements. Real-time RT-PCR and microarray analysis showed no change in expression of TGF-beta1, TGF-beta2, TGF-beta3, or bone morphogenetic proteins-2 and -4, yet immunohistochemical staining for phosphorylated SMAD2, an indicator of TGF-beta signaling, and for phosphorylated SMAD1/5/8, an indicator of signaling through the bone morphogenetic proteins, showed the highest percentage of positively stained cells in the proximal aortic segments of occluded animals. For TGF-beta signaling, this increase was significantly different than for sham-operated controls. Western blot analysis showed no difference in total TGF-beta1 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 TGF-beta, but not altered expression, may be a major mechanism regulating early hypertensive vascular remodeling.
Popovic
Natasa
N
Department of Systems Biology and Translational Medicine, TAMHSC, 336 Reynolds Medical Bldg., College Station, TX 77843-1114, USA.
Bridenbaugh
Eric A
EA
Neiger
Jessemy D
JD
Hu
Jin-Jia
JJ
Vannucci
Marina
M
Mo
Qianxing
Q
Trzeciakowski
Jerome
J
Miller
Matthew W
MW
Fossum
Theresa W
TW
Humphrey
Jay D
JD
Wilson
Emily
E
D000818:Animals; D001011:Aorta / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D001017:Aortic Coarctation / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015153:Blotting, Western; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D030541:Databases, Genetic; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D006973:Hypertension / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D012039:Regional Blood Flow / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D018615:Ultrasonography, Doppler, Color
D019485:Bone Morphogenetic Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta