Besides an elevated blood pressure, the spontaneously hypertensive rat (SHR) has multiple microvascular complications including endothelial apoptosis with capillary rarefaction. The SHR also has elevated levels of proteolytic (e.g. matrix metalloproteinase, MMP) activity and apoptosis in microvascular cells compared to its normotensive control, but the specific enzymes involved and the molecular mechanism for apoptosis are unknown. We hypothesize that selected MMPs cleave the extracellular domain of vascular endothelial growth factor receptor-2 (VEGFR-2), which in turn causes endothelial apoptosis and capillary rarefaction. Zymographic analysis shows that gelatinase (MMP-2 and MMP-9) and matrilysin (MMP-7) activities are significantly enhanced in SHR plasma. The SHR has lower levels of the extracellular domains of VEGFR-2 in cardiac microvessels. Furthermore, application of plasma from the SHR, or purified MMP-9 and MMP-7 to naïve cells causes cleavage of the extracellular domain of VEGFR-2. The receptor cleavage was blocked by broad-acting MMP inhibitors (GM6001 1 microM, EDTA 10 mM, or doxycycline 11.3 microM). Chronic MMP inhibition (doxycycline, 5.4 mg/kg/day, 24 weeks) attenuated VEGFR-2 cleavage, endothelial apoptosis, and capillary rarefaction in the SHR. These results suggest elevated plasma MMP activities may cleave VEGFR-2, resulting in endothelial apoptosis and capillary rarefaction in the SHR.