FoxO1 activation protects against IL-6-mediated perinatal metabolic programming of lung micro-vessels

Introduction: Obesity triggers lung diseases. We showed that maternal obesity promotes proliferation of lung smooth muscle cells (SMC) through an IL-6-FoxO1 axis in offspring. These processes are also central in the pathogenesis of pulmonary arterial hypertension (PAH). However, it remains elusive if maternal obesity causes PAH. Aims: (1) To investigate the impact of maternal obesity on lung micro-vessels in the offspring, and if it is IL-6 dependent; (2) To analyze if Paclitaxel, an anti-proliferative FoxO1 activator, protects against vascular remodeling. Methods: (1) Female wildtype (WT) and IL-6-/- mice were fed high-fat diet (HFD) or standard diet (SD) prior mating, and during gestation and lactation. After weaning, offspring of both groups received SD. (2) At postnatal day (P) 50, offspring were treated with intravenous Paclitaxel. Lungs were harvested at P21 and P70. Results: (1) Increased microvascular muscularisation, medial wall thickness and micro-vessel formation at P70 were linked to more proliferating (ki67-positive) vascular SMC at P21 in WTHFD when compared to WTSD. Gene expression of endothelial and pro-angiogenetic markers was elevated at P21; moreover, laser-microdissected vessels and bronchi showed reduced FoxO1 mRNA and altered FoxO1 target genes in WTHFD at P21. IL-6-/-HFD offspring were protected from these changes. (2) Paclitaxel treatment protected WTHFD offspring from remodeling and proliferation of vSMC. Conclusion: Maternal obesity is a potential risk factor for PAH via an IL-6-FoxO1 mediated hyperplasia of vSMC HFD offspring. FoxO1 activation could be a novel preventive strategy in the therapy of early metabolic origins of cardiovascular diseases.