Pulmonary Iymphangioleiomyomatosis (LAM), a rare progressive lung disease associated with mutations of the Tuberous Sclerosis Complex (Tsc2) tumor suppressor gene, manifests by neoplastic growth of LAM cells, induction of cystic lung destruction and respiratory failure. LAM severity correlates with up-regulation in serum of the prolymphangiogenic vascular endothelial growth factor D (VEGF-D) that distinguishes LAM from other cystic diseases. The goal of our study was to determine whether Tsc2-deficiency up-regulates VEGF-D and whether axitinib, the FDA-approved small molecule inhibitor of VEGFR signaling, will reduce Tsc2-null lung lesion growth in a mouse model of LAM. Our data demonstrate up-regulation of VEGF-D in the serum and lung lining in mice with Tsc2-null lesions. Progressive growth of Tsc2-null lesions induces recruitment and activation of inflammatory cells and increased nitric oxide production. Recruited cells isolated from the lung lining of mice with Tsc2-null lesions demonstrate up-regulated expression of pro-vasculogenic Vegfa, pro-lymphangiogenic Figf and pro-inflammatory Nos2, Il6, Ccl2 genes. Importantly, axitinib is an effective inhibitor of Tsc2-null lesion growth and inflammatory cell recruitment which correlates with reduced VEGF-D levels in serum and lung lining. Our data demonstrate that pharmacological inhibition of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth, attenuates recruitment and activation of inflammatory cells and reduces VEGF-D levels systemically and in the lung lining. Our study suggests a potential therapeutic benefit of inhibition of VEGFR signaling for treatment of LAM.