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<p>Vascular endothelial dysfunction because of environmental mercuric chloride (HgCl<sub>2</sub>) exposure is well known to induce cardiovascular diseases and heightened vascular responsiveness to angiotensin II (Ang 1–8). The PI3K/AKT/eNOS signaling pathway is essential for preserving endothelial NO bioavailability. Nevertheless, the reasons underlying this dysfunction during oxidative stress are inadequately elucidated.&#xa0;This study explored the roles of <span>l</span>-arginine (LA) and tetrahydrobiopterin (BH<sub>4</sub>) both alone and in combination on Ang1-8-induced vascular responses via the endothelial PI3K/AKT/eNOS pathway against HgCl<sub>2</sub> -induced vascular dysfunction in rat aortic rings.&#xa0;In comparison to control (CT) rings; HgCl<sub>2</sub> markedly modified Ang1-8 vascular reactivity, consistent with eNOS uncoupling and oxidative dysregulation. Inhibition of PI3K or AKT further amplified these effects, thereby confirming the vasoprotective role of the PI3K/AKT/eNOS system. The co-administration of LA and BH<sub>4</sub> significantly restored both Emax and pD<sub>2</sub> values in the presence of HgCl<sub>2</sub> and inhibitors, indicating improved NO bioavailability and re-coupled eNOS activity.&#xa0;Treatments of LA and BH4 together sustained endothelial PI3K/AKT/eNOS signaling and alleviate HgCl<sub>2</sub>-induced vascular hyperreactivity to Ang1-8 through restoration of NO/cGMP-mediated relaxation, reduces oxidative damage, and enhances antioxidant capacity. These results highlight a potential therapy strategy focused on resolving substrate-cofactor coupling and reinstating endothelial signaling to mitigate heavy metal-induced vascular dysfunction.</p>

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Role of l-Arginine and Tetrahydrobiopterin in Attenuation of Vascular Ang1-8 Reactivity via Endothelial PI3K/AKT/eNOS Signaling Pathways in HgCl2-Induced Vascular Dysfunction. An Ex-Vivo Study

  • 期刊论文

  • 发表日期：

    2026年6月15日

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  • Zana Hassan Ibrahim,
  • Ridha Hassan Hussein,
  • Ismail Mustafa Maulood

摘要

Vascular endothelial dysfunction because of environmental mercuric chloride (HgCl2) exposure is well known to induce cardiovascular diseases and heightened vascular responsiveness to angiotensin II (Ang 1–8). The PI3K/AKT/eNOS signaling pathway is essential for preserving endothelial NO bioavailability. Nevertheless, the reasons underlying this dysfunction during oxidative stress are inadequately elucidated. This study explored the roles of l-arginine (LA) and tetrahydrobiopterin (BH4) both alone and in combination on Ang1-8-induced vascular responses via the endothelial PI3K/AKT/eNOS pathway against HgCl2 -induced vascular dysfunction in rat aortic rings. In comparison to control (CT) rings; HgCl2 markedly modified Ang1-8 vascular reactivity, consistent with eNOS uncoupling and oxidative dysregulation. Inhibition of PI3K or AKT further amplified these effects, thereby confirming the vasoprotective role of the PI3K/AKT/eNOS system. The co-administration of LA and BH4 significantly restored both Emax and pD2 values in the presence of HgCl2 and inhibitors, indicating improved NO bioavailability and re-coupled eNOS activity. Treatments of LA and BH4 together sustained endothelial PI3K/AKT/eNOS signaling and alleviate HgCl2-induced vascular hyperreactivity to Ang1-8 through restoration of NO/cGMP-mediated relaxation, reduces oxidative damage, and enhances antioxidant capacity. These results highlight a potential therapy strategy focused on resolving substrate-cofactor coupling and reinstating endothelial signaling to mitigate heavy metal-induced vascular dysfunction.