Introduction: Stroke is a growing health problem in women. We previously showed that ischemia/reperfusion (I/R) in male rats reduced tone in middle cerebral arteries (MCA) but enhanced tone in parenchymal arterioles (PA). Tissue plasminogen activator (tPA) may contribute to vascular dysfunction, oxidative stress and inflammation. However, vascular dysfunction and the effect of tPA have not been studied in females.
Hypothesis: I/R in ovariectomized (OVX) female rats impairs MCA and PA function differentially, increases vascular oxidative stress and intravascular polymorphonuclear neutrophils (PMN). tPA has an additive effect on the vascular dysfunction after I/R.
Methods: OVX female rats underwent 2 h MCA filament occlusion (n=16) or sham surgery (n=17) with 30 min reperfusion. tPA (1 mg/kg, i.v.) or vehicle (Vh) was given 10 min prior to reperfusion. Myogenic tone and reactivity to nitric oxide synthase (L-NNA, 10-4M) and Rho kinase (Y27632, 10-8 to 10-5M) inhibition were measured in pressurized MCA and PA. MCA were stained for F-actin and 3-nitrotyrosine (NT), a marker of oxidative stress. Brain intravascular PMN were identified with myeloperoxidase and collagen IV using immunohistochemistry, and counted blinded to group.
Results: In MCA, I/R decreased tone at 75 mmHg (Sham Vh: 26±3%, Sham tPA: 27±3% vs. MCAO Vh: 21±2%, MCAO tPA: 21±3%, P<0.05) and reduced constriction to L-NNA (Sham Vh: 35±3%, Sham tPA: 34±2% vs. MCAO Vh: 20±3%, MCAO tPA: 25±3%, P<0.01) with no effect on dilation to Y27632. In PA, myogenic tone (at 40 mmHg) and reactivity to L-NNA and Y27632 was not affected by I/R. PA were less sensitive to Y27632 than MCA after I/R with tPA (EC50: 2.0±0.5 vs. 0.8±0.1 μM, P<0.05). F-actin and NT in the MCA were not affected by I/R or tPA. The number of PMN was small (<0.8±0.3/mm2) in all groups but there was a trend to increased ipsilateral intravascular PMN after I/R with tPA.
Conclusions: The differential effect of I/R on MCA vs. PA in OVX females on tone suggest parenchymal blood flow may be restricted during reperfusion that could increase perfusion deficits. tPA had no effect on tone in MCA and PA but might enhance intravascular PMN, implicated in no-reflow after I/R. Therapies to alleviate parenchymal vasoconstriction may improve stroke outcome in females.