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 ApoE-/- mice via continuous subcutaneous infusion
of angiotensin II (AngII). Using 3D 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 day 28 for aortic morphology, nerve density, vascularization,
and inflammation. Both serial and delayed denervation significantly
reduced sympathetic nerve density, approximating normal levels. Delayed
denervation trended towards improved survival (87%) by reducing rupture
risk after treatment, while serial denervation prevented early ruptures
but showed diminishing benefits after mid-point 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.