Estrogen Inhibits Vascular Calcification via Vascular RANKL System

Abstract

Key Words: RANKL Ⅲ vascular calcification Ⅲ BMP-2 Ⅲ MGP Ⅲ estrogen V ascular calcification is one of the major complications of cardiovascular disease and an independent risk factor for myocardial infarction and cardiac death, 1 among other outcomes. Arterial calcification is also associated with osteoporosis, especially in postmenopausal women. 2 Recent evidence strongly suggests the biological linkages on both disease mechanisms based on the presence of bone-related proteins 3 and bone-related cells at the site of calcification. 4 Accordingly, a triad of key proteins in bone metabolism has emerged as new players in cardiovascular diseases: RANK (the receptor activator of nuclear factor B), the RANK ligand (RANKL), and osteoprotegerin (OPG).In bone, RANKL and OPG are expressed in osteoblasts, and the receptor RANK is expressed in osteoclast cells. The major role of RANKL in bone is the stimulation of osteoclast activity 5 and inhibition of osteoclast apoptosis. 6 RANKL binds not only to RANK but also to OPG,7,8 which is secreted as a soluble protein that lacks transmembrane and cytoplasmic domains. Because of this peculiarity of a decoy receptor, the major biological action described for OPG has been through the binding to RANKL and consequent inhibition of RANK stimulation, then decreasing the osteoclast differentiation and activity in bone. 7,8 OPG-deficient mice develop severe osteoporosis resulting from marked increase in osteoclast activation, and interestingly two-thirds of the animals have profound vascular medial calcification. 9 Similar to OPG-deficient mouse phenotype, postmenopausal women also have high incidence of osteoporosis and vascular calcification, 10 which suggests that RANK-RANKL system may work not only in osteoporosis but also in arterial calcification.

Estrogen Receptor Control of Atherosclerotic Calcification and Smooth Muscle Cell Osteogenic Differentiation

“…The relationship in younger postmenopausal women is now well established; however, the paucity of studies in older postmenopausal women limits our understanding of E2 effects in this context, although studies are now addressing this issue. 36,37 Replicating the postmenopausal state in animal models is challenging, and E2 replacement after ovariectomy elicits dramatic effects on plaque progression and lipid profiles 27 ; thus, such studies tend to replicate findings in studies of younger postmenopausal women. The use of gonadally intact animals, by us and others, 38 avoids the need to interpret the E2 effect on total plaque area caused by altered plasma cholesterol levels; however, the limitation associated with use of intact animals is the pharmacological levels of E2 achieved in the blood.…”

“…25 However, other studies have demonstrated an inhibitory role for E2 in VSMC calcification in vitro. 26,27 In the context of atherosclerosis, studies support a protective effect of E2 on plaque calcification in women, based on the cardiovascular protective effects of E2 that reduce total plaque burden, attributable to modulation of traditional risk factors, such as plasma high-density lipoprotein and low-density lipoprotein. 28,29 In the clinic, studies show low serum E2 levels associate with increased coronary artery calcification (CAC), [30][31][32] whereas E2 replacement in younger menopausal women reduces CAC.…”

“…33,34 These findings are supported by animal studies that show E2 protects against atherosclerotic plaque calcification when associated with beneficial effects on plaque progression. 27,35 However, the mechanistic similarities to bone formation suggest that estradiol could promote vascular calcification in certain circumstances. This dilemma continues to raise the question of how estrogens impact on vascular calcification and plaque progression in the longer term, particularly in the aging vasculature, 36,37 where established, more advanced lesions show a reduced antiatherosclerotic response to exogenous estrogen treatment in females.…”

Anti-Osteoporotic Drugs and Vascular Calcification: The Bidirectional Calcium Traffic

“…At molecular level, estrogens down-regulate tumor necrosis factor (TNF)-α, which is found in both bone tissue and atheromas, and enhance VSMC calcification in vitro [79], and RANKL, which also plays a major role in both ectopic and physiologic calcification [80,81]. In addition, in cultured aortic VSMCs from adult ovariectomized pigs, 17β-estradiol, but not raloxifene, attenuated transdifferentiation induced by a calcifying medium and decreased the expression of bone sialoprotein [82].…”

OxPL

“…[18][19][20] Vascular calcification and osteoporosis are both active biological processes, which share common mechanisms, including the BMP pathway, Wnt Pathway, and OPG. 15,21,22 Osteogenic bone formation in the heart has become the third axis in the triad hypothesis of CAVD as shown in the Figure. However, the role of statins in the field of CAVD has been elusive. All of the randomized clinical trials have been negative to date.…”