Pharmacological targeting of vegfr signaling with axitinib inhibits tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis

Elena N. Atochina-Vasserman, Elena Abramova, Melane L. James, Ryan Rue, Amy Y. Liu, Nathan Tessema Ersumo, Chang Jiang Guo, Andrew J. Gow, Vera P. Krymskaya

Результат исследований: Материалы для журналаСтатья

5 Цитирования (Scopus)

Аннотация

Pulmonary lymphangioleiomyomatosis (LAM), a rare progressive lung disease associated with mutations of the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene, manifests by neoplastic growth of LAM cells, induction of cystic lung destruction, and respiratory failure. LAM severity correlates with upregulation in serum of the prolymphangiogenic vascular endothelial growth factor D (VEGF-D) that distinguishes LAM from other cystic diseases. The goals of our study was to determine whether Tsc2 deficiency upregulates VEGF-D, and whether axitinib, the Food and Drug Administration-approved small-molecule inhibitor of VEGF receptor (VEGFR) signaling, will reduce Tsc2-null lung lesion growth in a mouse model of LAM. Our data demonstrate upregulation 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 upregulated expression of provasculogenic Vegfa, prolymphangiogenic Figf, and proinflammatory Nos2, Il6, and 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.

Язык оригиналаАнглийский
Страницы (с-по)L1447-L1454
ЖурналAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Том309
Номер выпуска12
DOI
СостояниеОпубликовано - 2015
Опубликовано для внешнего пользованияДа

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology
  • Physiology

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  • Цитировать

    Atochina-Vasserman, E. N., Abramova, E., James, M. L., Rue, R., Liu, A. Y., Ersumo, N. T., Guo, C. J., Gow, A. J., & Krymskaya, V. P. (2015). Pharmacological targeting of vegfr signaling with axitinib inhibits tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis. American Journal of Physiology - Lung Cellular and Molecular Physiology, 309(12), L1447-L1454. https://doi.org/10.1152/ajplung.00262.2015.