Estrogen Replacement Treatment in Diabetic Ovariectomized Female Rats Potentiates Postischemic Leukocyte Adhesion in Cerebral Venules

Abstract

Background and Purpose-Chronic 17␤-estradiol (E 2 ) replacement therapy in ovariectomized (OVX) female rats reduces leukocyte adhesion and brain damage after transient forebrain ischemia. Recently, we found that E 2 treatment in diabetic OVX females was associated with enhanced postischemic neuropathology. We tested the hypothesis that in chronically hyperglycemic diabetic OVX females, chronic E 2 replacement potentiates post-transient forebrain ischemia leukocyte adhesion. Methods-Pial venules were observed through closed cranial windows. Adherence of rhodamine 6G-tagged leukocytes was monitored before and 10 hours after transient forebrain ischemia (20 minutes right common carotid artery occlusion plus hemorrhagic hypotension) in intact, untreated OVX and E 2 -treated OVX females rendered diabetic via streptozotocin. Leukocyte adhesion was quantitated as the percentage venular area occupied by adherent leukocytes. Results-At 2 hours after transient forebrain ischemia, a similar low level of leukocyte adhesion was seen in the 3 groups (Ͻ3% of the venular area). Starting at Ϸ4 hours after ischemia, leukocyte adhesion in the E 2 -treated OVX females rose to significantly higher levels compared with the other groups. Relative to the 2-hour value, the level of adhesion at 10 hours was 12.5-fold, 4-fold, and 5-fold greater in the E 2 -treated OVX, OVX, and intact groups, respectively. Leukocyte extravasation (beginning after 6 hours of reperfusion) was observed in a majority (64%) of the E 2 -treated animals, with limited or no extravasation seen in the intact or OVX groups. Conclusions-These results suggest that factors associated with diabetes and chronic hyperglycemia convert E 2 from a counterinflammatory to a proinflammatory substance in an ischemic setting.

Vascular Adhesion Protein-1 Plays an Important Role in Postischemic Inflammation and Neuropathology in Diabetic, Estrogen-Treated Ovariectomized Female Rats Subjected to Transient Forebrain Ischemia

“…First, in agreement with a recent report from our laboratory (Xu et al, 2004), chronic E 2 replacement therapy in diabetic OVX female rats was associated with substantial time-dependent increases in cerebral leukocyte adhesion, over the initial 6 h of reperfusion after forebrain ischemia. Subsequently, neutrophil infiltration was observed.…”

“…Arterial partial CO 2 pressure and partial O 2 pressure measurements obtained before 20 min of ischemia, at the end of ischemia, and during 10 h of reperfusion (series 1) remained between 32 and 38 mm Hg and Ͼ100 mm Hg, respectively, during the entire study. As commonly seen with this model (Xu et al, 2004), endischemic arterial pH was significantly lower than the preischemic value in all experimental groups (mean Ϯ S.D. end-ischemic versus preischemic values for all groups were 7.39 Ϯ 0.02 versus 7.48 Ϯ 0.02, respectively).…”

“…for 7 days). Previous work from our laboratory demonstrated that the 0.1-mg/kg daily dose of E 2 results in an average daily plasma E 2 concentration that falls between the peak and nadir levels observed over the normal rat estrous cycle (Xu et al, 2004).…”

“…Results from our laboratory suggest that whether leukocytes contribute to ischemic neuropathology or not depends on whether leukocyte (principally neutrophil) (Arumugam et al, 2005) infiltration and not simply venular adhesion has occurred during the initial 10 to 12 h of reperfusion. Thus, the extent of neuropathology assessed after several days of reperfusion (Santizo et al, 2002) seemed to parallel the patterns of acute neutrophil extravasation (over 10 h of reperfusion), as viewed in pial venules in situ (Xu et al, 2004). It is relevant to note that these experiments were performed on diabetic, intact, ovariectomized (OVX), and estrogen-treated OVX females to test the hypothesis that chronic estrogen replacement therapy is associated with a potentiation of postischemic inflammation and neuropathology, opposite to what was previously observed in nondiabetic females (Santizo et al, 2000b).…”

Microvascular reactions of normal and osteoporotic bones in response to surgical interventions

“…In fact, there is currently no consensus on the magnitude or pathologic role of leukocyte adhesion in nonskeletal tissues after OVX. OVX has been reported to enhance PMN accumulation in the brain of resting animals (Santizo et al, 2000) but other data indicated that OVX does not influence the PMN adherence in the brain tissue after transient ischemia (Xu et al, 2004). We suggest that these differences in baseline leukocyte adhesion might be explained by the different timelines.…”