Estradiol modulates post-ischemic cerebral vascular remodeling and improves long-term functional outcome in a rat model of stroke

Abstract

We previously observed that 17β-estradiol (E2) augments ischemic borderzone vascular density 10 days after focal cerebral ischemia-reperfusion in rats. We now evaluated the effect of E2 on vascular remodeling, lesional characteristics, and motor recovery up to 30 days after injury. Peri-lesional vascular density in tissue sections from rats treated with 0.72 mg E2 pellets was higher compared to 0.18 mg E2 pellets or placebo (P) pellets: vascular density index, 1.9 ± 0.2 (0.72 mg E2) vs. 1.4 ± 0.2 (0.18 mg E2) vs. 1.5 ± 0.4 (P), p=0.01. This was consistent with perfusion magnetic resonance imaging (MRI) measurements of lesional relative cerebral blood flow (rCBF): 1.89 ± 0.32 (0.72 mg E2) vs. 1.32 ± 0.19 (P), p=0.04. Post-ischemic angiogenesis occurred in P-treated as well as E2-treated rats. There was no treatment-related effect on lesional size, but lesional tissue was better preserved in E2-treated rats: cystic component as a % of total lesion, 30 ± 12 (0.72 mg E2) vs. 29 ± 17 (0.18 mg E2) vs. 61 ± 29 (P), p=0.008. Three weeks after right middle cerebral artery territory injury, rats treated with 0.72 mg E2 pellets used the left forelimb more than P-treated or 0.18 mg E2-treated rats: limb use asymmetry score, 0.09 ± 0.43 (0.72 mg E2) vs. 0.54 ± 0.12 (0.18 mg E2) vs. 0.54 ± 0.40 (P), p=0.05. We conclude that treatment with 0.72 mg E2 pellets beginning one week prior to ischemia/reperfusion and continuing through the one-month recovery period results in augmentation of lesional vascularity and perfusion, as well as improved motor recovery.

High-dose estrogen treatment at reperfusion reduces lesion volume and accelerates recovery of sensorimotor function after experimental ischemic stroke

“…As timing and dose of E2 administration can influence the level of neuroprotection or neurodamage (Strom et al, 2009), it was important to understand these parameters in the current experimental paradigm. We've previously shown that the 0.72mg 60-day release IRA pellet sustains supraphysiologic levels from 1-10 days after implantation with a gradual decline to high physiologic levels by 30 days (Ardelt et al., 2012). Additional time points from the current study revealed that this pellet produces supraphysiologic levels > 2000 pg/mL as early as 30 minutes after implantation, with a peak at 2 hours of > 3200 pg/mL E2 ( Figure 2 ).…”

“…We have previously shown that administration of E2 one week prior to tMCAO in ovariectomized female rats enhanced post-stroke angiogenesis without significantly altering lesion size, which also resulted in an improvement in contralateral forelimb function three weeks after ischemic stroke (Ardelt et al, 2012). MRI demonstrated improvement in CBF during the fourth week of recovery with E2 pre-treatment.…”

Improved renal ischemia tolerance in females influences kidney transplantation outcomes

“…The ability to administer β-estradiol or any medication to reduce renal IRI in a transplantation setting depends on the persistence of its beneficial effects or, at a minimum, the lack of detrimental effects in the procurement of other organs. Sex differences in IRI tolerance are well described in cardiac tissue (7,31,32) and the nervous system (8,33), and short-term administration of 17β-estradiol directly improved IRI tolerance in rat livers (9) and myocardium (34) when given 1 and 3 hours before injury, respectively, making nonrenal off-target effects of lesser concern.…”

“…Sexual dimorphism with respect to tolerance of IRI has been noted in a number of laboratory animal models (7)(8)(9)(10)(11). Generally, there is consensus that female sex conveys greater tolerance of, or protection from, IRI relative to the male sex.…”

Estrogen-IGF-1 interactions in neuroprotection: Ischemic stroke as a case study

“…Subsequent studies also showed that this effect was dose dependent, in that post-stroke vessel density was greater with a 0.72mg estradiol pellet versus a low dose (0.18mg) or control pellet. The higher dose was also associated with functional recovery (Ardelt et al, 2012). Interestingly, in a study using male rats, 17b-estradiol treatment failed to increase microvessel density in the peri-infarct area, but preserved motor function in this group (Ulbrich et al, 2012).…”