Physical Activity and Vascular Adaptation: The Role of the ERK1/2 Pathway in mmLDL-Mediated Upregulation of ETA Receptors in Mouse Mesenteric Arteries

Abstract

Purpose: This study investigates the role of minimally modified low-density lipoprotein (mmLDL) in the upregulation of endothelin type A (ETA) receptors in mouse mesenteric arteries via the ERK1/2 pathway, with a particular focus on the modulation of this pathway by physical activity. Methods: Mice were randomly divided into five groups: normal saline (NS), mmLDL, mmLDL + U0126 (an ERK1/2 inhibitor), mmLDL + DMSO, and LDL. To integrate the impact of physical activity, additional subgroups were established where each main group's mice underwent regular treadmill exercise. Microvascular tonometry was used to observe the contraction volume-effect curves induced by the ETA agonist endothelin-1 (ET-1) in mesenteric arteries. Protein expression levels of ERK, phosphorylated ERK (p-ERK), and ETA receptor were measured by Western Blot. mRNA levels of the ETA receptor were quantified by RT-PCR, and protein expression on mesenteric arteries was assessed using immunofluorescence assays.

Results: Treatment with mmLDL significantly enhanced the ET-1 contractile volume-effect curve, with an increase in Emax value from 179.63±3.93% in the NS group to 291.44±12.67% (P<0.001). This was accompanied by significant increases in both mRNA and protein expression levels of the ETA receptor and p-ERK. After administration of U0126, vasoconstrictor responses were notably reduced, with Emax values decreasing to 202.28±5.88% (P<0.001), alongside significant decreases in mRNA and protein expression levels of ETA receptors and p-ERK. Importantly, physically active mice showed attenuated responses to mmLDL with less pronounced increases in ETA receptor and p-ERK expression, suggesting a protective role of exercise against mmLDL-induced vascular changes.

Conclusion: mmLDL upregulates ETA receptors in mouse mesenteric arteries by activating the ERK1/2 signaling pathway. Our findings also reveal that physical activity can modulate this molecular pathway, possibly offering protective effects against mmLDL-induced vascular dysfunction. These results highlight the potential of regular physical exercise to mitigate adverse vascular responses mediated through the ERK1/2 pathway, suggesting a promising intervention for enhancing vascular health in conditions characterized by elevated mmLDL levels. Further research is needed to explore the mechanisms by which physical activity influences this pathway and to assess its clinical implications in human populations.