Mathematical Biology Seminar Michael Sanderson, Univ of Mass Medical School Wednesday March 28, 2007 2:55pm LCB 219 Regulation of smooth muscle cell contraction of airways and blood vessels in the lung: Modeling explains the experiments. Abstract: The contraction of airway and arteriole smooth muscle cells (SMCs) is a key event in asthma and pulmonary hypertension. However, the Ca2+ signaling mechanisms that regulate the onset of contraction or relaxation are not well understood. We investigated the contractile and Ca2+ signaling responses of SMCs to ACH, 5HT and KCl in small airways and arterioles within mouse lung slices using time-lapse and confocal microscopy. The major finding was that agonist-induced Ca2+ oscillations cause contraction in both airway and arteriole SMCs. Importantly, the magnitude of the contraction was determined by the frequency of the Ca2+ oscillations and suggests that SMC contraction is frequency-modulated. However, the relationship of FM-regulation differs between airway and arteriole SMCs; arteriole SMCs respond with a larger contraction to slow frequency oscillations. In response to KCl, both the airway and arteriole SMCs exhibit low frequency Ca2+ oscillations but this correlated with spasmodic contraction. The extent of contraction of the SMCs was also determined by the Ca2+ sensitivity of the specific SMC. In SMCs prepared with caffeine and ryanodine, the Ca2+ concentration could be manipulated. While elevations in Ca2+ resulted in an initial airway SMC contraction, the sustained elevation in Ca2+ resulted in relaxation of the airway but not the arteriole SMCs. Mathematical modeling of these responses supports the hypothesis that the relaxation rate is a key parameter integrating the Ca2+-induced contractile force. These data indicate that different responses of different SMC types can be mediated by variations in the actin-myosin interactions and raise the possibility that, in the disease state, changes in the relaxation rates can lead to hyper-contractility.