Increased Intimal Hyperplasia After Vascular Injury in Male Androgen Receptor-Deficient Mice

Abstract

Intimal hyperplasia is a vascular pathological process involved in the pathogenesis of atherosclerosis. Data suggest that T, the most important sex steroid hormone in males, protects men from atherosclerotic cardiovascular disease. T mainly acts via the androgen receptor (AR), and in this study we evaluated formation of intimal hyperplasia in male AR knockout (ARKO) mice using a vascular injury model. Two weeks after ligation of the carotid artery, male ARKO mice showed increased intimal area and intimal thickness compared with controls. After endothelial denudation by an in vivo scraping injury, there was no difference in the reendothelialization in ARKO compared with control mice. Ex vivo, we observed increased outgrowth of vascular smooth muscle cells from ARKO compared with control aortic tissue explants; the number of outgrown cells was almost doubled in ARKO. In vitro, stimulation of human aortic vascular smooth muscle cells with a physiological T concentration inhibited both migration and proliferation of the cells. Analyzing the expression of central regulators of cell proliferation and migration, we found that mRNA and protein levels of p27 were lower in uninjured arteries from ARKO mice and that T replacement to castrated male mice increased p27 mRNA in an AR-dependent manner. In conclusion, AR deficiency in male mice increases intimal hyperplasia in response to vascular injury, potentially related to the effects of androgens/AR to inhibit proliferation and migration of smooth muscle cells.

The role of androgen receptors in atherosclerosis

“…Castration of wild-type mice increased neointimal lesion size following wire-induced injury but not following ligation of mouse femoral arteries in vivo, whereas selective deletion of AR from ECs or VSMCs had no effect on lesion size. This compares with a recent investigation reporting increased neointimal growth following ligation (but not following denuding injury) of the common carotid artery in (male) ARKO mice, compared with controls (Wilhelmson et al, 2016). In vitro investigations using aortic explants suggested this was due to increased VSMC proliferation and migration (which were shown to be inhibited by testosterone in human VSMCs in culture).…”

Gender, hyperandrogenism and vitamin D deficiency related functional and morphological alterations of rat cerebral arteries

“…VDD resulted in decreased AR protein expression in the artery wall of males but, surprisingly, not in that of females. The decreased protein expression might be deleterious in males, as endogenous androgens may protect against vascular remodeling [43, 44], atherogenesis [44–46] and thrombosis [47]; furthermore, it could also contribute to the preservation of NO bioavailability [43]. On the contrary, in females, VDD did not alter AR protein expression, which supports the findings that (i) short-term VDD alone does not cause alterations in cerebral vessels of females, and (ii) men are more seriously affected by the cerebrovascular consequences of VDD than healthy premenopausal women.…”

Sex differences in endothelial function important to vascular health and overall cardiovascular disease risk across the lifespan

“…Given that there are many changes that occur to the cardiovascular system with aging, this association does not necessarily prove "cause and effect." However, data in animal models using castration (3) or AR knockout models (249) suggest a direct association between testosterone and atherosclerosis. To our knowledge, there are no data in humans that demonstrate a cause-and-effect relationship between testosterone and atherosclerosis but it is an important area of investigation.…”