ACE2 Inhibits Dermal Regeneration Through Ang II in Tissue Expansion

Abstract

Background

Tissue expansion is a widely employed technique in reconstructive surgery aimed at addressing considerable skin defects. Nevertheless, matters like inadequate expansion capability and the potential for skin breakage due to the fragility of the expanded tissue present notable hurdles in enhancing skin regeneration during this process. Angiotensin-converting enzyme 2 (ACE2) is recognized for its essential role in facilitating tissue renewal and regeneration. However, its precise impact on skin renewal during tissue expansion remains underexplored. This study seeks to elucidate ACE2's contribution to skin regeneration, specifically examining its role in collagen synthesis.

Methods

This study evaluated the expression and distribution of ACE2 in expanded skin using samples derived from both rats and human patients. Additionally, we investigated ACE2 expression in stretched keratinocytes in vitro. ACE2 knockout keratinocytes were transfected with small interfering RNA (siRNA) and cocultured with fibroblasts to observe fibroblast proliferation and migration. MLN-4760 was utilized to inhibit the ACE2 enzymatic activity. Additionally, we analyzed parameters such as the size of expanded skin, dermal thickness, and the levels of collagen I (COL I), collagen III (COL III), and transforming growth factor β (TGF-β) to elucidate the role of ACE2 in the context of expanded skin.

Results

The thinning of the expanded dermis was linked with elevated ACE2 expression. Enzymatic activity and ACE2 expression were both increased by mechanical stress. Additionally, ACE2 utilized Ang II to activate the migration and proliferation of human dermal fibroblasts. In vivo, the ACE2 inhibitor MLN-4760 promoted skin regeneration and reduced dermal thinning by elevating COL I, COL III, and TGF-β during expansion.

Conclusions

This finding suggest that mechanical stretch increases ACE2 expression, which in turn promotes the regeneration of expanded skin. The basis for using ACE2 in clinical settings to increase tissue expansion efficacy is provided by this work.