Estrogen Regulation of Endothelial and Smooth Muscle Cell Migration and Proliferation

Abstract

Objective-Restenosis is a major limitation of percutaneous coronary intervention. Migration and proliferation of vascular cells remain a cornerstone in neointimal formation. The cardioprotection of estrogen is well recognized, but the intracellular mechanisms related to these beneficial effects are not completely understood. Methods and Results-We investigated the effects of 17␤-estradiol (17␤E) on mitogen-activated protein kinase (MAPK) activity and the migration and proliferation of porcine aortic endothelial cells (PAECs) and porcine smooth muscle cells (PSMCs). Treatment with 17␤E (10 Ϫ8 mol/L) abrogated p38 and p42/44 MAPK phosphorylation mediated by platelet-derived growth factor-BB as well as the migration and proliferation of PSMCs. In contrast, treatment with 17␤E (10 Ϫ8 mol/L) induced the phosphorylation of p38 and p42/44 MAPK and the migration and proliferation of PAECs. Interestingly, the effects of 17␤E on PSMCs and PAECs were reversed by selective estrogen receptor antagonists (tamoxifen, 4-OH-tamoxifen, and raloxifen). These results suggest that in PSMCs, 17␤E inhibits chemotactic and mitogenic effects of platelet-derived growth factor-BB as well as p38 and p42/44 MAPK phosphorylation. In contrast, 17␤E promotes in PAECs the phosphorylation of p42/44 and p38 MAPK as well as the migration and proliferation of these cells. Key Words: 17␤-estradiol Ⅲ smooth muscle Ⅲ endothelium Ⅲ mitogen-activated protein kinase R estenosis, occurring in 20% to 40% of patients, is currently the primary limitation of percutaneous transluminal coronary angioplasty. 1 Estrogens play an important role in bone maintenance, in the cardiovascular system, and in the growth, differentiation, and biological activity of various tissues. 2 Moreover, numerous in vivo studies in various animal models have demonstrated that the neointimal formation induced after balloon injury is increased in the absence of estrogen but is decreased in its presence. 3 The protective effects of 17␤-estradiol (17␤E) are related to favorable changes in the plasma lipid profile, 4 to the inhibition of vascular smooth muscle cell (VSMC) proliferation 5 and migration, 6 to the relaxation of coronary vessels through endothelial NO synthase (eNOS) activity, 7 and to the reduction of platelet and monocyte aggregation, 8 tumor necrosis factor-␣ release, 9 and extracellular matrix synthesis. 10 We have shown that local delivery of 17␤E reduces the neointimal thickness produced by coronary balloon injury in a porcine model. 11 Estrogen can bind 2 estrogen receptors (ERs), ER␣ and ER␤, which are expressed in all vascular cell types. 12 The classic genomic mechanism, or long-term effect of estrogen on vascular tissues, is dependent on a change in gene expression. Most recently, a second mechanism related to the direct effect of estrogen has been identified. 13 Several studies have demonstrated that 17␤E can activate many intracellular signaling responses. 14 The mitogen-activated protein kinase (MAPK) cascade plays a central role in the cellular signal transdu...

Olibanum Extract Inhibits Vascular Smooth Muscle Cell Migration and Proliferation in Response to Platelet-Derived Growth Factor

“…In this study, we explored the possible role of p38 MAPK and ERK 1/2, and the effects of olibanum on PDGF-induced RASMC migration and proliferation; JNK, an important isoenzyme of MAPK was not included because these two PDGF-induced RASMC responses (proliferation and migration) were not significantly suppressed by JNK inhibition in previous studies . The activation of p38 MAPK stimulated various cell functions such as contraction, migration, and proliferation in the vascular smooth muscle cells (Geraldes et al, 2002;Kim et al, 2004). PDGF-induced migration and proliferation was associated with p38 MAPK phosphorylation in RASMCs .…”

“…PDGF is known to induce signaling molecules that are associated with the activation of mitogen-activated protein kinases (MAPKs) (Pearson et al, 2001). MAPKs belong to a family of serine/threonine-specific protein kinases, consisting of three isoforms: extracellular signal-regulated kinase (ERK) 1/2, p38 MAPK, and stress-activated protein kinase/c-Jun N-terminal kinase (JNK) (Geraldes et al, 2002;Kim et al, 2004). These MAPKs are involved in the regulation of the migration and proliferation of vascular smooth muscle cells (Liu et al, 2007).…”

Estrogens and atherosclerosis: insights from animal models and cell systems

“…Furthermore, estrogens promote endothelial cell proliferation and survival. Several studies documented mitogenic effects of E 2 either acting alone or in combination with serumderived growth factors in endothelial cell cultures (Geraldes et al 2002, Sengupta et al 2004, Williams et al 2004, Kawagoe et al 2007, Oviedo et al 2011. Moreover, endothelial apoptosis initiated by TNFa, H 2 O 2 , or oxidized LDL was consistently inhibited in the presence of estrogens in a process involving activation of protein kinases MAPK and AKT, increased expression of anti-apoptotic proteins BCL2 and BCL-XL (BCL2L1), and disabling of the pro-apoptotic protein BAD (Alvarez et al 1997, Spyridopoulos et al 1997, Lu et al 2006, Florian & Magder 2008, Yu et al 2009).…”

New Frontiers in Cardiology

“…26 Recently, estradiol-eluting phosphorylcholine-coated stents (Abbott/Biocompatibles) implanted in porcine coronary arteries reduced neointimal hyperplasia by 40% compared with control stents. 27 EASTER (Estrogen and Stent to Eliminate Restenosis) was a single-center feasibility study testing 17-␤-estradiol-eluting BiodivYsio stents in 30 patients with de novo coronary lesions.…”