Abstract 9464: Adipocyte-Derived Fatty-Acid-Binding Protein 4 Impairs Human Dermal Microvascular Endothelial Cells Under Hypoxia Insults - A Mechanistic Clue to Impaired Wound Healing in Obesity

Abstract

Introduction: Dermal white adipose tissue is found in the dermis of the skin, which may participate in the wound healing process. Obesity-mediated adipocyte hypertrophy has been related to adipose tissue hypoxia and chronic low-grade inflammation, which may impair wound healing by suppressing the vascularity. Fatty-acid-binding protein (FABP) 4 is a cytosolic fatty acid chaperone expressed in adipocytes, which may be involved in the pathogenesis of some vascular diseases and was found upregulated in skin tissue of obese animals. This study aimed to investigate the potential mechanistic impacts of adipocyte-derived FABP4 on vascular cells for wound healing under hypoxia insults. Methods and Results: Primary human dermal microvascular endothelial cells (HDMECs) and adipocytes were used. FABP4 and inflammatory protein expressions such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β were upregulated under the hypoxic conditions. Treatment with conditioned medium from adipocytes under the hypoxic conditions significantly impaired cell function including migration and tube formation abilities in HDMECs. Furthermore, FABP4 and inflammatory protein expressions were upregulated, and angiogenic signaling pathways such as phospho-AKT/hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF)/ stromal cell-derived factor (SDF)-1 were downregulated in these conditioned medium treated HDMECs. Interestingly, administration of FABP4 inhibitor could reverse the conditioned medium-induced cell damages in HDMECs. On the other hand, FABP4 could directly impair cell functions with lower angiogenic and higher inflammatory protein expressions in HDMECs under the hypoxic conditions. Conclusions: Our pilot findings suggested that adipocyte hypoxia might lead to the secretion of inflammatory proteins and FABP4. Adipocyte-derived FABP4 could impair the migration and tube formation abilities of HDMECs via upregulating TNF-α/IL-6/IL-1β and downregulating phospho-AKT/HIF-1α/VEGF/SDF-1 signal pathways. Our findings provide a theoretical basis to the potential impact of FABP4 as a novel therapeutic target on wound healing in obese subjects with adipose tissue hypoxia.