Perivascular adipose tissue (PVAT), the fat layer surrounding blood vessels, is increasingly recognized as an active regulator of vascular function rather than a passive structural cushion. Yet whether PVAT contains functionally important sympathetic nerves has remained debated, largely because conventional two-dimensional imaging can miss sparse, spatially complex neural structures.

A study published in Life Metabolism by researchers from Fudan University now provides a three-dimensional view of sympathetic innervation in aortic PVAT (aPVAT). Led by Prof. Yan Tang and Prof. Qi-Qun Tang, the team identified a previously undescribed, hierarchically organized nerve network around the mouse aorta and showed that this local circuit is required for the blood pressure rise induced by cold exposure.

Using whole-mount immunolabeling, iDISCO+ tissue clearing, and light sheet microscopy, the researchers visualized tyrosine hydroxylase-positive sympathetic fibers in intact aPVAT at single-fiber resolution. Rather than a diffuse pattern, the nerves formed a trunk-to-branch architecture: a primary sympathetic trunk ran along the aortic arch and generated secondary fibers that entered the adipose tissue, traversed toward the vascular wall, wrapped around aPVAT surfaces, or connected adjacent fat lobules.

Retrograde tracing further showed that the left stellate ganglion was the predominant sympathetic source for this aPVAT innervation (Figure 1). Signals were also detected in thoracic dorsal root ganglia and weakly in the nodose ganglion, indicating that aPVAT may sit within a broader autonomic and sensory circuit rather than acting only as a passive route for nerves to reach the vessel.

Cold exposure strongly remodeled this network. After 72 h at 4°C, aPVAT sympathetic fibers showed higher density, larger diameter, and greater length, together with increased tyrosine hydroxylase (TH) and synaptophysin signals, consistent with enhanced local sympathetic activation and nerve-terminal remodeling.

The functional test was decisive. When the researchers locally ablated sympathetic nerves in aPVAT with 6-hydroxydopamine (6-OHDA), mice no longer developed the sustained increase in systolic and diastolic blood pressure normally caused by 2 weeks of intermittent cold exposure. This effect occurred without a significant reduction in circulating norepinephrine, supporting a local perivascular mechanism. By contrast, denervating inguinal white adipose tissue did not prevent cold-induced hypertension, underscoring the specificity of aPVAT.

Together, the findings redefine aPVAT as a sympathetic effector tissue and identify a localized neuro-adipovascular circuit that can amplify vascular responses to cold stress. The work also suggests a possible additional explanation for the cardiovascular effects of stellate ganglion blockade: beyond suppressing cardiac sympathetic output, such interventions may also influence sympathetic signaling to aPVAT. Because the study was performed in mice, its clinical relevance to human hypertension remains to be established. Future work will need to determine how aPVAT senses cold-related stress despite its location near the body core, how norepinephrine storage and release are regulated locally, and whether selective modulation of this circuit could provide a more precise strategy for treating sympathetically driven hypertension.
DOI
10.1093/lifemeta/loag015