Microvascular Theory of Exercise-Induced Bronchoconstriction in Asthma: Potential Implication of Vascular Endothelial Growth Factor

Exercise-induced bronchoconstriction (EIB) is used to describe the increase in airway resistance that follows exercise in asthmatic patients. To date, two major hypotheses, water- and heat-loss theory, have been put forward to explain the mechanism of EIB. However, there is increasing evidence that airway microcirculation has the potential to contribute to the pathophysiological mechanisms of EIB. Bronchial asthma is a chronic airway inflammatory disease associated with airway remodeling, including the growth and proliferation of new blood vessels. Airway microvascular remodeling is likely to be induced by several growth factors, such as vascular endothelial growth factor (VEGF). VEGF has powerful effects on vascular function and also increases microvascular permeability. In this respect, high expression of VEGF in asthmatic airways contributes to the pathogenesis of EIB via increased airway microvascular permeability. Moreover, endothelial cells in airway microcirculation stimulated by high levels of VEGF is sensitive to exercise challenge and therefore, the change in circulating thrombomodulin levels with exercise can be an index of functional properties in endothelial cells. In this review, we will demonstrate the possible roles of VEGF on EIB in asthmatic patients in details. I will then propose a molecular mechanism explaining the microvascular theory of EIB based on functional abnormalities of endothelial cells in newly generated microvessels in asthmatic airways. These findings suggest that the intervention against VEGF offers a possible new strategy for the treatment of EIB in asthmatic patients.