Exploring the Impact of Nitric Oxide and Epidermal Growth Factor Receptor on Vascular Remodeling Induced by Mechanical Stretch
Authors: Zeidan Asad , Ghantous Crystal , Djouhri Laiche 
Published: May 2024

Hypertension is a key risk factor in many cardiovascular diseases like heart failure, kidney failure and vascular hypertrophy. Mechanical stretch/hypertension, promotes vascular smooth muscle cells remodeling by inducing leptin expression and other hypertrophic proteins like ERK1/2, AKT, and cofilin. Also the Epidermal growth factor receptor (EGFR) transactivation has shown to mediate vascular remodeling by enhancing VSMC hypertrophy, migration, and proliferation. Nitric oxide (NO) has been shown to be a critical factor for many cellular physiological function, it has the ability to induce VSMC relaxation leading to reduce hypertension. Moreover NO has received extensive attention as an anti- hypertrophic agent. Several Studies have shown that nitric oxide does not only promote vasodilation but it also inhibits VSMC proliferation. The major aim of this study was to investigate the inhibitory effect of NO and the effect of blocking the EGFR in mechanical stretch induced vascular remodeling. Methods: Rat portal veins (RPVs) were isolated and pretreated with/without NO donor (SNAP) or EGFR kinase blocker (AG1478) and then stretched to study their effects on mechanical stretch induced leptin synthesis and VSMC remolding. Western blot analysis was done to detect protein expression for leptin, adiponectin, eNOS p-ERK1/2 and p-AKT. Immunocytochemistry was performed on rat aortic vascular smooth muscle (RASMC) to detect GATA-4 nuclear translocation. Moreover, we used laser confocal microscopy on frozen RPV sections to detect the level of ROS formation and leptin. Finally, we performed qPCR for adiponectin, adipoR1 and adipoR2 mRNA. Results: In this study we showed the effect of mechanical stretch at different time points (1hour and 24 hours). Mechanical stretch-induced leptin expression was mediated by ERK1/2, AKT activations and ROS formation. These effects were associated with eNOS and adiponectin downregulation. Mechanical stretch had no effect on the expression of adiponectin receptors (adipoR1 and adipoR2). RASMCs pretreated with 3.1 nmol/L for 3 hours had induced GATA-4 nuclear translocation. Pre-incubation the RPV with SNAP significantly decreased mechanical stretch induced leptin expression, ERK1/2 and AKT phosphorylation. Moreover, SNAP significantly inhibited the adiponectin downregulation by mechanical stretch. Leptin-induced GATA-4 nuclear translocation was inhibited by SNAP. The involvement of EGFR transactivation in mechanical stretch-induced leptin expression was investigated using AG1478. Pretreatment of RPVs with AG1478 had no effect on mechanical stretch-induced early leptin expression (1 hour) while it inhibited mechanical stretch-induced late leptin expression (24 hours), ROS formation, and adiponectin and eNOS downregulation. However, treatment with AG1478 showed no effect on leptin-induced GATA-4 nuclear translocation. Conclusion: This study showed that NO has a direct inhibitory effect on mechanical stretch-induced AKT and ERK1/2 pathways and inhibits ROS formation that leads to vascular remodeling. On the other hand, EGFR transactivation was able to mediate mechanical stretch-induced vascular hypertrophy via ROS formation and leptin production, thus making EGFR and NO a promising therapeutic target for hypertension induced hypertrophy.

This work was funded by Qatar University grants award UREP27-050-3-020 from Qatar National Research Fund (a member of Qatar Foundation) to AZ.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.