ERalpha Protects Against Lipoprotein‐Associated Oxidative Stress to Regulate Vascular Tone in Both Male and Female Mice

Lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1) is a major vascular scavenger receptor for binding and cellular uptake of oxidized low‐density lipoproteins (oxLDL). LOX‐1 is an important mediator of oxLDL‐stimulated pathways that trigger vascular dysfunction, inflammation, and oxidative stress. However, the mechanisms protecting against lipoprotein‐related oxidative stress to maintain normal vascular tone are understudied. Here we investigated the connection of ERalpha‐activated vascular protection with the oxidative status of vascular rings. We preincubated male and female aortic vessels with 10 μM ox‐LDL for 30 minutes, and after measuring phenylephrine contractile responses, treated the aortas with 10 −12 to 10 −5 μM of 4,4′,4″‐(4‐propyl‐[1H]pyrazole‐1,3,5‐triyl)tris‐phenol (PPT), a specific ERalpha agonist. We found that PPT induced relaxation in aortic rings preincubated with ox‐LDL in both sexes, demonstrating a vascular protective role of ERalpha in lipoprotein‐associated oxidative stress. Given the interplay between ERalpha signaling and lipoprotein‐associated oxidative stress, we evaluated the expression level of LOX‐1 in PPT‐stimulated mouse endothelial cells in vitro . Western blot analysis shows that LOX‐1 expression was attenuated in endothelial cells following treatment with PPT. Collectively, these data suggest a protective role of ERalpha against lipoprotein‐associated oxidative stress in regulating vascular tone. Moreover, we anticipate these studies will provide a broader look into intracellular signaling mechanisms that influence vascular tone and events. Support or Funding Information Supported by 5K12HD043451