Estradiol and Progestins Differentially Modulate Leukocyte Infiltration After Vascular Injury

Abstract

Background-Inflammation plays an important role in the response to endoluminal vascular injury. Estrogen (17␤-estradiol, E 2 ) inhibits neointima formation in animal models, and the progestin medroxyprogesterone acetate (MPA) blocks this effect. This study tested the hypothesis that E 2 inhibits the migration of inflammatory cells, particularly granulocytes, into the rat carotid arteries after acute endoluminal injury and that MPA blocks this effect. Methods and Results-Ovariectomized rats were randomly divided into subgroups and treated with E 2 , MPA, E 2 ϩMPA, or vehicle and subjected to balloon injury of the right carotid artery. After 1, 3, or 7 days, rats were euthanized, and carotid arteries (injured and control) were analyzed for inflammatory cells by flow cytometry. At 1 day, granulocytes (HIS48 ϩ and CD45 ϩ ), monocyte/macrophages (Mar1 ϩ and CD45 ϩ ), and T lymphocytes (CD3 ϩ and CD45 ϩ ) were increased 26-fold, 12-fold, and 3-fold, respectively, in injured compared with contralateral control arteries of vehicle-treated rats. Granulocytes and monocyte/macrophages decreased markedly by 3 days. E 2 reduced the granulocyte and monocyte/macrophage populations of injured vessels by Ϸ50% and increased T lymphocytes. MPA had no independent effect on inflammatory cells but completely blocked the effect of E 2 . Immunohistochemical examination verified these findings and localized inflammatory cells to the adventitial and periadventitial domains of injured vessels. Conclusions-E 2 may limit the neointimal response to endoluminal vascular injury, at least in part, by limiting leukocyte entry from adventitial/periadventitial tissues into injured vessels early in the injury response.

Sex differences and estrogen modulation of the cellular immune response after injury

“…This injury to the carotid artery is associated with infiltration of leukocytes including phagocytes, granulocytes, and lymphocytes in the adventitia surrounding the site of injury [53,54]. Ovariectomized rats have a significant leukocyte infiltrate following arterial injury [55]. Consistent with this observation, estrogen treatment of OVX rats yielded a decrease in migration of neutrophils and monocytes into the damaged artery, suggesting a protective effect [55].…”

“…Ovariectomized rats have a significant leukocyte infiltrate following arterial injury [55]. Consistent with this observation, estrogen treatment of OVX rats yielded a decrease in migration of neutrophils and monocytes into the damaged artery, suggesting a protective effect [55]. In the rat model of acute vascular injury, expression of mRNA in the common carotid artery for adhesion molecules P-selectin, vascular cell adhesion molecule-1, and ICAM-1, as well as chemoattractants CINC-2β and monocyte chemoattractant protein-1 (MCP-1), are increased in injured arteries of OVX rats at 2 hours.…”

Sex Difference in Vascular Injury and the Vasoprotective Effect of Valsartan Are Related to Differential AT 2 Receptor Expression

“…Progesterone has reported to block the effect of estrogen. 17,18 Therefore, there is a possibility that progesterone plays some role in the enhancement of vascular remodeling in ovariectomized mice. However, our group has previously reported that increased neointimal formation, DNA synthesis, and atherosclerotic lesions in ovariectomized mice were reversed by treatment with estrogen to the physiologic (female) level, 9,10 suggesting that estrogen contributes to improvements in vascular remodeling over and above the apparent opposite effects of progesterone.…”

Effects of Combined Oral Conjugated Estrogens and Medroxyprogesterone Acetate on Brain Infarction Size after Experimental Stroke in Rat

“…In injured brain, coadministration of MPA with CEE may reverse estrogen's favorable effects on migratory inflammatory cells and potentiate vascular endothelial disruption (Xing et al, 2004) or heighten glutamate-induced excitotoxic injury (Nilsen and Brinton, 2002a, b). Alternatively, it is possible that subcortical brain regions may be more dependent on blood flow, making striatum more susceptible to postischemic vascular obstruction.…”