The NE-adrenergic receptor axis drives osteoarthritis progression via neurovascular cross-talk: a dual-responsive...

Osteoarthritis (OA) progression is strongly driven by the dysregulated interplay between the sympathetic nerve and abnormal vascularization, severely affecting patients' physical and mental well-being. In this study, temporomandibular joint osteoarthritis (TMJ-OA) was induced in mice using a unilateral anterior crossbite (UAC) model. We found that sympathetic nerve activation promoted pathological angiogenesis and vasoconstriction, whereas blocking sympathetic nerves inhibited both processes. Furthermore, during disease progression, hyperinnervation by sympathetic nerves in the subchondral bone region preceded vascular changes, with both elements exhibiting prominent spatial co-localization. Single-cell RNA sequencing analysis identified a specific expansion of β-2 adrenergic receptor positive (Adrb2⁺) vascular endothelial cells in OA, which was closely linked to vascular growth and contraction. In vitro experiments confirmed that norepinephrine (NE) released from sympathetic nerves enhanced the migration and tube-forming capacity of endothelial progenitor cells (EPCs), while significantly upregulating the expression of Rho Guanine Nucleotide Exchange Factor 12 (Arhgef12) and Endothelin 1 (Edn1), thereby promoting vasoconstriction. Nevertheless, local delivery of ADRB2 specific blocker ICI118551 via responsive 3-aminophenylboronic acid- and aldehyde-dual-modified sodium alginate/protocatechuic acid-grafted polyethyleneimine hydrogel could effectively inhibit the sympathetic nerve-blood vessel crosstalk by blocking ADRB2 signaling, thereby inhibiting excessive angiogenesis and vasoconstriction. Our findings offered mechanistic insights into the regulation of pathological angiogenesis and vasoconstriction in osteoarthritis, and supported the rational development of strategies to suppress aberrant vascularization for osteoarthritis treatment.