Abstract 602: Depot-Specific Angiogenic Pathways in Human Adipose Tissue: Changes With Type 2 Diabetes

Abstract

Emerging evidence suggests that impaired adipose tissue (AT) angiogenesis leads to metabolic dysfunction. Differences in angiogenesis between the omental (OM) and subcutaneous (SC) depots were previously reported. The peri-pancreatic fat (PF) mass correlates with BMI in humans and may be a significant contributor to local inflammation in islets in type2 diabetes (T2D); however this depot was not yet characterized in humans. The aim of this project was to determine the depot-specific angiogenesis in human obesity and T2D. OM, SC and PF fat were collected from obese non-diabetic (ND) subjects (BMI>33). Capillary density assessed as CD31 immuno-positivity was 1.25-fold higher in the SC vs. OM AT (p=0.0033). Angiogenic sprouting from matrigel embedded AT explants showed a 1.3-fold increase in the number of branches in SC compared to OM (p<0.05). Unexpectedly, the PF explants showed a complete absence of sprouting in similar conditions. To identify changes in angiogenic genes, we used RT 2 Profiler TM Human Angiogenesis PCR Pathway-Focused Array. In OM AT the highest pro-angiogenic expressors were FGF-1 and CXCL6. PF fat showed a 13-fold higher expression of thrombospondin-1 (TSP1) as well as a 13-fold down-regulation of VEGF-C compared to the SC. This result suggests that TSP1 may be key for the angiogenic suppression in PF. We also examined functional angiogenesis and gene expression in OM and SC from T2D subjects (BMI>33, HbA1c>6.5%). In T2D, capillary density was decreased for SC (p=0.0065) and OM (p=0.0896) AT vs ND. Capillary sprouting in OM and SC explants was significantly reduced by 40% in T2D samples compared to ND. Gene expression of CD34 + CD31 + endothelial cells (EC) isolated from T2D SC showed a 4-17 fold down-regulation of CXCL6, IL-6, and IL-8 as well as HIF-1α compared to OM suggesting reduced hypoxia and inflammation. Also, TSP1 was 4-fold increased in EC from OM of T2D subjects. In conclusion, T2D OM and SC fat displayed reduced functional angiogenesis in vitro compared to ND. Gene expression analysis suggests depot-specific pathways regulating angiogenesis in obesity and T2D. TSP1 emerges as a key inhibitor of angiogenesis in human AT and the absence of functional angiogenesis in PF AT is of significance as it could contribute to peri-islet inflammation.