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Mast Cells Can Mediate Vascular Permeability through Regulation of the PI3K–HIF-1–VEGF Axis

¹ Department of Internal Medicine and Airway Remodeling Laboratory and ² Department of Anatomy, Chonbuk National University Medical School, Jeonju, South Korea

Correspondence and requests for reprints should be addressed to Yong Chul Lee, M.D., Ph.D., Department of Internal Medicine, Chonbuk National University Medical School, San 2-20, Geumam-dong, Deokjin-gu, Jeonju, 561-180, South Korea. E-mail: leeyc{at}chonbuk.ac.kr

Rationale: Bronchial inflammation is usually accompanied by increased vascular permeability. Mast cells release a number of mediators that act directly on the vasculature, resulting in vasodilatation, increased permeability, and subsequent plasma protein extravasation. Vascular endothelial growth factor (VEGF) has been implicated to contribute to asthmatic tissue edema through its effect on vascular permeability. However, the effects of mast cells on VEGF-mediated signaling in allergic airway disease are not clearly understood.

Objectives: An aim of the present study was to investigate the role of mast cells on VEGF-mediated signal transduction in allergic airway disease.

Methods: We used genetically mast cell–deficient WBB6F₁-Kit^W/Kit^W-v (W/W^v) mice and the congenic normal WBB6F₁^+/+ mouse model for allergic airway disease to investigate the role of mast cells on VEGF-mediated signal transduction in allergic airway disease, more specifically in vascular permeability.

Measurements and Main Results: Our present study, with ovalbumin (OVA)-sensitized without adjuvant and OVA-challenged mice, revealed the following typical pathophysiologic features of allergic airway diseases: increased inflammatory cells of the airways, airway hyperresponsiveness, increased vascular permeability, and increased levels of VEGF. However, levels of VEGF and plasma exudation in W/W^v mice after OVA inhalation were significantly lower than levels in WBB6F₁^+/+ mice. Moreover, mast cell–reconstituted W/W^v mice restored vascular permeability and VEGF levels similar to those of the WBB6F₁^+/+ mice. Our data also showed that VEGF expression was regulated by hypoxia-inducible factor-1 (HIF-1) activation through the phosphatidylinositol 3-kinase (PI3K)–HIF-1 pathway in allergic airway disease.

Conclusions: These results suggest that mast cells modulate vascular permeability by the regulation of the PI3K–HIF-1–VEGF axis.

Key Words: mast cells • vascular permeability • vascular endothelial growth factor • allergy • inflammation

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Mast cells are believed to contribute to the development of allergic airway disease accompanied by increased vascular permeability and plasma exudation. What This Study Adds to the Field Mast cells can regulate vascular leakage, at least in part via modulation of the PI3K–HIF-1–VEGF axis in mice.