Temporal effects of sympathetic denervation on aortic remodeling and rupture in experimental abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a life-threatening condition with no effective pharmacologic therapies, and increasing evidence suggests that the sympathetic nervous system (SNS) contributes to disease progression. However, the temporal effects of SNS modulation on AAA stability remain unclear. To investigate the impact of SNS modulation on aneurysm outcomes, we induced AAAs in male <i>ApoE</i>^-/- mice via continuous subcutaneous infusion of angiotensin II. Using three-dimensional light sheet microscopy, we found that ruptured AAAs exhibited the highest sympathetic innervation in experimental aneurysms. Sympathetic denervation was performed using intraperitoneal 6-hydroxydopamine, administered either serially (before and during AAA induction) or at a delayed time point (after aneurysm formation). Mice were monitored for mortality, and surviving animals were evaluated at <i>day 28</i> for aortic morphology, nerve density, vascularization, and inflammation. Both serial and delayed denervation significantly reduced sympathetic nerve density, approximating normal levels. Delayed denervation trended toward improved survival (87%) by reducing rupture risk after treatment, whereas serial denervation prevented early ruptures but showed diminishing benefits after midpoint treatment. Both serial denervation and delayed denervation increased intima-media thickness and reduced aortic wall collagen content. Despite these structural changes, no significant differences in vascularization or macrophage infiltration were observed across groups. These findings demonstrate that sympathetic denervation influences aneurysm stability through vascular remodeling, independent of angiogenesis or macrophage infiltration, underscoring the importance of SNS modulation at specific stages of AAA progression.<b>NEW & NOTEWORTHY</b> This study reveals the temporal effects of sympathetic denervation on aneurysm stability in an experimental model of AAA. Using 3-D light sheet microscopy, we demonstrate that ruptured AAAs exhibit the highest sympathetic innervation. Although delayed denervation reduced rupture risk and improved survival, serial denervation altered vascular remodeling. These findings establish SNS modulation as a key regulator of aneurysm progression and highlight the importance of timing in potential therapeutic interventions.