Estrogen Restores Postischemic Sensitivity to the Thromboxane Mimetic U46619 in Rat Pial Artery

Abstract

The objectives of the study were to (1) characterize the dose-response relationship to the TXA 2 analog, U46619 (0.01, 0.1, and 1 lmol/L) after global cerebral ischemia, (2) determine whether chronic 17b-estradiol (E2) replacement alters this relationship, and (3) determine if E2's mechanisms are transduced through cognate estrogen receptors. Rats were assigned to five groups (n ¼ 6): placeboimplanted ovariectomized (OVX) females, OVX plus chronic E2 (CE), OVX plus acute E2 (AE), OVX plus chronic E2 plus the estrogen receptor inhibitor ICI 182,780 (CEI), and OVX plus acute E2 plus ICI 182,780 (AEI). Rats were anesthetized, intubated, cannulated (femoral artery and vein), fitted with a closed cranial window, and subjected to 15-min reversible forebrain ischemia (4-vessel occlusion, 4-VO) and 60 mins of reperfusion. Arterial blood gases, intrawindow pressure, and temperature were controlled. Vessel diameter was measured before and 5 mins after superfusion of each concentration of U46619. Compared with preischemic responses, contractile response to U46619 was depressed at all concentrations after ischemia in the OVX group. In the chronic E2 and acute E2 groups, contractile response to 1 lmol/L of U46619 was normalized to near baseline values. However, in the CEI and the AEI groups, postischemic vasoconstriction was similar to that observed in the OVX rats. We conclude that E2 targets the cerebral microvasculature to preserve postischemic pial artery reactivity and that the effect is receptor mediated. Restoration of normal constriction to vascular agonists may be an important mechanism by which E2 protects the vasculature and diminishes tissue damage after ischemia.

Effects of Estrogen on Postischemic Pial Artery Reactivity to ADP

“…Postischemic vasomotor dysfunction [1,5,27,39] and loss of myogenic tone [11] in the cerebral vasculature have been previously reported and may reflect Ischemia-induced endothelial and/or vascular smooth muscle (VSM) injury. In the present study, we used two different agents*ADP (a partially endothelium/NO-dependent vasodilator) and PGE 2 (an endothelium/NO-independent vasodilator)*to evaluate pial arterial vascular function after a transient global ischemic insult.…”

“…After ovariectomy or E2 treatment, rats were caged for a period of at least seven days until the day of the experiment. These estrogen doses were chosen based on previous work in our laboratory showing that the slow-release pellets produce stable range of physiologically relevant estrogen levels between seven and 21 days after implantation [27]. Terminal blood samples were collected at the end of the experimental protocols, and plasma estrogen was measured by radioimmunoassay, using commercially available kits (Coat-a-Count; DPC, Los Angeles, California, USA).…”

“…There are a paucity of data regarding the effects of chronic estrogen replacement on pial arteriole reactivity after ischemic injury and whether these effects might be detrimental or protective. Our previous work demonstrates that estrogen affords some protection of postischemic vascular responsiveness [27], including endothelium, NO‐dependent vasodilation to acetylcholine (ACh) [39]. However, it is unclear if chronic estrogen replacement can also partially preserve postischemic pial artery responsiveness to other dilators, such as ADP.…”

Reproductive Senescence Blunts Response of Estrogen Receptor-α Expression to Estrogen Treatment in Rat Post-Ischemic Cerebral Microvessels

“…The ovaries were located and the ovarian arteries and veins were clamped and ligated. The ovaries were excised [14], and the abdominal muscle and skin were closed with 3.0 silk sutures.…”

“…The common carotid arteries were dissected through a midline anterior neck incision. Ligatures were placed around both carotid arteries and were reversibly occluded for 15 minutes to induce 4 vessel ischemia as previously described [14]. After 15 minutes the ligatures were removed and the brain allowed to spontaneously reperfuse for 120 minutes.…”