ROBO/SLIT in Obesity‐dependent Changes in Angiogenesis and Lung Regeneration

Abstract

More than 35 million people in the US suffer from chronic lung diseases, and a number of these patients have pre-existing conditions including obesity. Although lung transplantation is one of the options for end-stage lung diseases, due to the shortage of donors and low survival rate, this approach is suboptimal. In particular, there is an association between obesity and a poor outcome in lung transplantation. Thus, stimulating the regenerative ability of the lungs could be one of the therapeutic strategies for end-stage lung diseases in obese patients. Angiogenesis –the formation of new blood vessels- plays an important role in lung regeneration. Obesity is accompanied by endothelial cell dysfunction. However, the effects of obesity on lung vascular and alveolar regeneration remain unclear. Here we found that compensatory lung growth after unliteral pneumonectomy (PNX) was inhibited in leptin-deficient ob/ob mice treated with a high-fat diet compared to that in control lean mice. RNA sequencing analysis demonstrates that the levels of endothelial guidance molecules such as Roundabout proteins (ROBO/SLIT), which contribute to angiogenesis, are significantly higher in post-PNX obese mouse lungs compared to those from lean mouse lungs. The mRNA levels of Robo1, 2, and 4 and Slit2 are higher in the mouse lung tissues collected from post-PNX obese mice compared to those from lean mouse lungs when analyzed using quantitative RT-PCR. Network analysis reveals that the genes listed in the top 20 BP GO terms of cellular responses including cell migration, cell proliferation and extracellular matrix assembly interact with ROBO/SLIT during post-PNX lung growth. These results suggestthat ROBO/SLIT signaling may mediate the inhibition of post-PNX regenerative lung growth in obese mice. ROBO/SLIT may be the key signaling mechanism to restore lung regeneration in obese population.