Negative pressure mechanical signal increases the phosphorylation of eNOS Ser1177 by upregulating HSP90 expression to promote wound angiogenesis.

BACKGROUND

Chronic wound pathogenesis involves impaired angiogenesis. While negative pressure wound therapy (NPWT) clinically promotes angiogenesis, its biomechanical mechanisms remain unclear.

METHODS

A mechanical stretching model simulating NPWT was established in vitro. Multiomics approaches (single-cell sequencing, Ch-IP, Co-IP, and molecular docking) were employed to dissect HSP90-related regulatory networks. Typical molecular biological techniques are used to detect the expression of relevant proteins. Moreover, a rat dorsal wound model was used for the animal experiments.

RESULTS

NPWT-induced mechanical stimulation activates the GNAS/CREB1/HSP90 axis, increasing HSP90 transcription via CREB1 nuclear translocation. Elevated HSP90 displaces Cav-1 to augment eNOS Ser1177 phosphorylation, driving angiogenesis to promote wound healing. Pharmacological or genetic disruption of GNAS/CREB1 suppresses HSP90 expression and angiogenic capacity.

CONCLUSION

This study reveals a GNAS-mediated mechanotransduction pathway that activates HSP90-dependent eNOS signaling to accelerate wound angiogenesis, suggesting novel targets for therapeutic intervention.