Matrix metalloproteinase (MMP) inhibition eliminates training‐induced collateral blood flow expansion in rats

Abstract

To study the role of MMPs in collateral vessel remodeling, adult male Sprague-Dawley rats with bilateral femoral artery occlusion (n=30) were divided into sedentary (Sed, limited to cage activity, n=10) or treadmill exercise (Tr, 2x/d, 2 wks; n=20). Rats in Sed or Tr group were fed with either water or MMP inhibitor doxycycline (Doxy; ~30 mg/kg/d) for two wks. Hind limb blood flow was determined with isotope labeled microspheres during treadmill running. In Tr animals, Doxy treatment reduced MMP-2 protein content by 19% (Western blot); and proMMP-2 activity by 17% (Zymograph) in the red gastrocnemius muscle when compared with the water controls. Blood pressure (~130 mmHg) and heart rate (~480 bpm) were no difference across the groups during flow measuring. Collateral dependent blood flows to the calf muscle were 48±1.7, 47±8.7, 81±4.1 and 60±3.5 ml/min/100g in Sed+water (n=6), Sed+Doxy (n=4), Tr+water (n=9), and Tr+Doxy (n=8) groups respectively (ANOVA, p<0.001). Maximal luminal diameters of collateral artery (the perforating a.) increased from ~280μm in Sed groups to 317±13.7μm (Tr +water), and reduced to 278±11.3μm by Doxy in the Tr animals. Our results indicate that exercise training-induced remodeling of collateral function and structure requires normal MMP-2 function. Supported by NIH HL-37387.