Targeting the ERK Signaling Pathway to Halt Adventitia Remodeling of Ascending Thoracic Aortic Aneurysm

Ascending thoracic aortic aneurysms (AsTAAs) are life-threatening and lack effective drug treatments. This study investigated whether abnormal mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) activation in adventitial pericytes contributes to aneurysm progression. Human AsTAA tissue showed vasa vasorum remodeling and displaced pericytes. Isolated AsTAA-pericytes showed increased MEK/ERK signaling, proliferation, migration, proteolytic activity, proinflammatory secretome, and altered angiogenic function. These changes were reversed by the MEK inhibitor PD0325901. In a mouse model, short-term MEKi treatment reduced aortic dilatation, improved compliance, preserved elastin, and lessened inflammation, without adverse effects. This is the first study identifying dysregulated adventitial pericytes as a hallmark of AsTAA, supporting MEKi as a promising therapeutic.