Liver vitronectin release into the bloodstream increases due to reduced vagal muscarinic signaling after cerebral stroke in female mice

Abstract

Vitronectin (VTN) is a glycoprotein enriched in the blood and activates integrin receptors. VTN blood levels increase only in female mice 24 h after an ischemic stroke and exacerbate brain injury through IL‐6‐driven inflammation, but the VTN induction mechanism is unknown. Here, a 30 min middle cerebral artery occlusion (MCAO) in female mice induced VTN protein in the liver (normally the main source) in concert with plasma VTN. Male mice were excluded as VTN is not induced after stroke. MCAO also increased plasma VTN levels after de novo expression of VTN in the liver of VTN−/− female mice, using a hepatocyte‐specific (SERPINA1) promoter. MCAO did not affect SERPINA1 or VTN mRNA in the liver, brain, or several peripheral organs, or platelet VTN, compared to sham mice. Thus, hepatocytes are the source of stroke‐induced increases in plasma VTN, which is independent of transcription. The cholinergic innervation by the parasympathetic vagus nerve is a potential source of brain‐liver signaling after stroke. Right‐sided vagotomy at the cervical level led to increased plasma VTN levels, suggesting that VTN release is inhibited by vagal tone. Co‐culture of hepatocytes with cholinergic neurons or treatment with acetylcholine, but not noradrenaline (sympathetic transmitter), suppressed VTN expression. Hepatocytes have muscarinic receptors and the M1/M3 agonist bethanechol decreased VTN mRNA and protein release in vitro via M1 receptors. Finally, systemic bethanechol treatment blocked stroke‐induced plasma VTN. Thus, VTN translation and release are inhibited by muscarinic signaling from the vagus nerve and presents a novel target for lessening detrimental VTN expression.

Vitronectin Destroyed Intestinal Epithelial Cell Differentiation through Activation of PDE4-Mediated Ferroptosis in Inflammatory Bowel Disease

“…What is more, further analysis showed that PDE4B and PDE4D played a critical role in VTN-mediated ferroptosis. In addition to ferroptosis and cell differentiation, further investigation was needed to explore the other function of VTN in IBD in the future, including intestinal mucosal immunity, drug resistance, and intestinal fibrosis, and whether VTN regulated the phosphorylation of PDE4 in an integrin-dependent manner could be confirmed in next work, although the studies have confirmed that intergern was activated by VTN stimulation [ 26 , 47 , 48 ]. However, further studies are required to elucidate the mechanism regulating the VTN expression under physiological or pathological conditions, even whether there is a positive feedback loop between VTN-ferroptosis.…”