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1 Department of Clinical and Experimental Therapeutics Program, University of Georgia College of Pharmacy, Augusta, GA, USA; Department of Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA
2 Department of Clinical and Experimental Therapeutics Program, University of Georgia College of Pharmacy, Augusta, GA, USA
3 Department of Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA
4 Department of Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA; Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, USA
* To whom correspondence should be addressed. E-mail: aergul{at}mail.mcg.edu.
Degradation of the extracellular matrix proteins by matrix metalloproteinases (MMP) is an important regulatory step in the vascular remodeling process. Recent studies demonstrated that ETA receptors regulate cardiac MMP activity and fibrosis in DOCA-salt hypertension. However, little is known about ET-1 regulation of vascular MMP activity in hypertension. Thus, early changes in ET-1-mediated regulation of MMP activity were measured in borderline hypertensive rats (BHR), which develop impaired vasorelaxation and hypertension with chronic exposure to stress. Experiments were performed after 10 days of exposure to the behavioral stressor, air-jet stress, but prior to the onset of stress-induced hypertension. Study groups were 1) control (n=8); 2) air jet stress for 10 days (n=8); 3) control plus ETA antagonist ABT627 (n=4), and 4) air jet stress plus ETA antagonist (n=4). MMP activity in the thoracic aorta was assessed by gelatin zymography. MMP protein and tissue ET-1 levels were evaluated by immunohistochemistry and ET receptor density was determined by immunoblotting. Exposure to stress caused a 2-fold increase in plasma ET-1 levels (p<0.05) and there was increased ET-1 staining at the tissue level . Total MMP activity and expression of MMP-2 and MMP-9 were increased in the stress group. ETA receptor antagonism prevented the increase in MMP expression and activation in the stress group. These results provide evidence that the MMP system is activated before the development of hypertension and ET-1 mediates these early events in vascular remodeling.
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