Molecular reprogramming of adventitial pericytes by a selective MEK inhibitor halts the progression of thoracic aortic aneurysm
Authors: Mohammed Khaled AK , Avolio Elisa , Alvino Valeria V , Ahmed Eltayeb Mohamed , Rajakaruna Cha , Ghoneim Ahmed , Elminshawy Ahmed , Angelini Gianni D , Madeddu Paolo 
Published: February 2025

Aim

Reconstructive surgery is a life-saving treatment for individuals with advanced thoracic aortic aneurysms (TAAs) at risk of rupture. No effective pharmacological treatments are available to halt aortic dilatation before it reaches this critical point. Unravelling the cellular and molecular pathways involved in TAA formation and expansion is fundamental for identifying potential treatment targets. This study challenged the hypothesis that pericyte dysfunction destabilizes the adventitial vascular niche, hence compromising the ascending aorta’s elastic characteristics. We also investigated whether blocking the mitogen-activated extracellular signal-regulated kinase (MEK) pathway could slow TAA progression in a mouse model.

Methodology

Comparative histology and morphometry studies were performed on human ascending TAA and non-aneurismatic control tissues to quantify adventitia vasa vasorum (VV) size and abundance, and pericyte coverage and density. Proliferation, migration, and angiogenesis experiments were used to evaluate the functional phenotype of pericytes before and after blocking the MEK signalling pathway with PD0325901. In a mouse model with moderate TAA, we investigated the therapeutic efficacy of PD0325901 (10 mg/kg/d orally for 14 days) on TAA progression.

Results

The histological study of TAA samples demonstrated VV remodelling and reduced pericyte VV coverage due to increased detachment. Cultured TAA pericytes exhibited aberrant behaviour, including increased proliferation, migration, matrix metalloprotease activity, disrupted angiogenic capacity, and altered secretome, and MEK overactivation. PD0325901 restored pericyte contractile phenotype and angiogenic capacity, influencing their secretome, migratory capacity, and matrix formation/degradation equilibrium. In vivo, PD0325901 remarkably decreased aortic dilatation, increased compliance, retained medial elastin content, and reduced adventitial inflammation. No harmful consequences were noted.

Conclusion

This work identifies pericyte dysfunction related to MEK overactivation as a major contributor to TAA progression. This suggests that inhibiting the MEK signalling pathway could be a potential treatment option for TAA before surgical intervention becomes necessary.

Clinical Perspective

What is new?

Thoracic aortic aneurysm (TAA) remains a major clinical challenge due to its asymptomatic progression and risk of life-threatening rupture. Our study highlights the crucial role of adventitial pericytes in maintaining vascular homeostasis and preventing aneurysm-related vascular remodeling.

We demonstrate that dysregulated MEK/ERK signaling drives aortic adventitial pericyte dysfunction, leading to microvascular instability, extracellular matrix degradation, chronic inflammation, and progressive aneurysm expansion.

Importantly, we show that the clinically available MEK inhibitor, PD0325901, effectively restores pericyte function, preserving adventitial vascular integrity, reducing inflammatory cytokine production, and stabilizing the aortic wall.

In a preclinical mouse model, PD0325901 significantly attenuated aneurysm growth, improved aortic wall compliance, and prevented maladaptive vascular remodeling.

What Are the Clinical Implications?

Our findings provide strong translational evidence supporting MEK inhibition as a promising therapeutic strategy to halt TAA progression and enhance aortic wall resilience, offering a potential medical alternative to delay or prevent surgical intervention.