Abstract 1309: Selective Estrogen Receptor Beta Activation Attenuates Atherogenesis: Potential Role in Regulating the Survival of Vascular Progenitor Cells
Introduction: Estrogen receptor β (ERβ) has emerged as a key receptor in the vessel wall that shows up-regulated mRNA expression after vascular injury in male rats (Lindner 1998). Moreover, in the coronary arteries of females ERβ is the predominant estrogen receptor and its expression correlates with the degree of calcification (Christian, 2006).
Hypothesis: We hypothesized that selective ERβ activation protects against the development of experimental atherosclerosis. Moreover, as bone marrow-derived vascular progenitor cell (VPCs) appear to participate in arterial repair and lesion formation we postulated that these cells express ERβ and their survival can be modulated by selective ERβ activation.
Method: Female atherosclerosis-prone ApoE null mice were ovariectomized before being fed an atherogenic diet and receiving daily s.c. injections of either the selective ERβ modulator 8β-VE2 (100μg/kg, n=7) or vehicle (n=5) for 5 weeks. VPCs were grown in culture from human peripheral blood mononuclear cells or mouse bone marrow.
Results: Systemic administration of 8β-VE2 resulted in a 36% reduction in atherosclerotic lesion area for the entire aorta, and a 40% reduction in the aortic arch lesion area while total serum cholesterol levels remained constant. Mice receiving 8β-VE2 had less complex atherosclerotic aortic lesions (e.g., early fatty streaks) compared to advanced complex lesions in vehicle treated mice. Importantly, treatment with 8β-VE2 did not appear to modulate ERα activity as uterine weight - a parameter that is closely regulated by ERα-remained constant. Using immunolabeling and Western blotting, we detected ERβ expression in bone marrow-derived monocytes, macrophages and VPCs. Electron microscopy localized ERβ expression in the mitochondria and nuclei of VPCs. In vitro, 8β-VE2 alone did not affect VPC survival, however, caused up to a 40% augmentation of hydrogen peroxide-induced VPC apoptosis (p,0.01).
Conclusions: Selective activation of ERβ attenuates atherogenesis and accelerates VPC apoptosis. Together these observations suggest important new therapeutic avenues for vasculoprotection.