Targeting MEK signalling with PD0325901 halts aortic dilatation and wall stiffening in a murine model of thoracic aortic aneurysm

Abstract Background Thoracic aortic aneurysm (TAA) is a fatal condition marked by progressive aortic dilation and weakening. Currently, treatment is limited to surgical intervention, as no pharmacological therapies effectively prevent disease progression. Aberrant activation of the mitogen-activated extracellular signal-regulated kinase (MEK) pathway has been implicated in vascular remodelling and aneurysm formation. This study explores the therapeutic potential of PD0325901, a selective MEK inhibitor (MEKi), in mitigating TAA progression in a murine model. Purpose This study aimed to assess the effectiveness of MEK inhibition with PD0325901 to reduce aortic dilation, maintain vascular integrity, and decrease arterial stiffness in a mouse model of Angiotensin II (ANG-II)-induced TAA. Methods Fourteen male C57BL/6J mice (8 weeks old) underwent continuous ANG-II infusion (1000 ng/kg/min) via subcutaneous osmotic minipumps to induce TAA. After 72 hours, mice were randomized into a treatment group (n=7) receiving oral PD0325901 (10 mg/kg/day) and a vehicle group (n=7) receiving oral DMSO for 14 days. A control group (n=5) with no ANG-II infusion was included for reference. Aortic dimensions and pulsed wave velocities (PWV) were assessed via echocardiography at baseline and study endpoint. Mice were euthanized, and aortas were collected for histological, immunohistochemistry, and Western blot analyses. Results Western blot confirmed successful MEK inhibition in the treatment group. ANG-II infusion significantly increased the diameters of the ascending aorta and aortic arch, while PD0325901 treatment markedly reduced aneurysm formation compared to the vehicle group. The increase in ascending aortic diameter from baseline to final echocardiography was significantly lower in the treated group vs. the vehicle group (P<0.01). Similarly, aortic arch dilation was significantly reduced in the treated group compared to the vehicle group (P<0.05). PWV, a marker of arterial stiffness, was significantly lower in the treated group (P<0.0001). Wall shear stress remained unchanged across groups. Histological analysis showed that PD0325901 preserved aortic media structure, reduced elastin degradation (P<0.05), and inhibited collagen deposition and fibrosis (P<0.001). Immunohistochemistry revealed preserved vascular smooth muscle cell α-SMA expression in the media (p<0.001) and reduced CD45+ inflammatory cell infiltration (p<0.05) in the adventitia of treated mice. Additionally, PD0325901 decreased adventitial cell apoptosis (p<0.001) while maintaining PDGFRβ+ cell density. No treatment-related mortality was observed. Conclusions PD0325901 treatment effectively blunted aortic dilatation, preserved aortic wall integrity, and reduced arterial stiffness in a mouse ANG-II-induced model. These findings highlight selective MEK inhibition as a promising pharmacological strategy to limit aneurysm expansion and potentially delay the need for surgical intervention.