Kenneth A Barbee1, Jaimit B Parikh2, Yien Liu1, Donald G Buerk1, Dov Jaron1. 1. School of Biomedical Engineering, Science and Health Systems, Drexel University, 3140 Market St., Bossone 704, Philadelphia, PA 19104 USA. 2. IBM Thomas J. Watson Research Center, 1101 Kitchawan Rd., Yorktown Heights, NY USA 10598.
Abstract
INTRODUCTION: Colocalization of endothelial nitric oxide synthase (eNOS) and capacitative Ca2+ entry (CCE) channels in microdomains such as cavaeolae in endothelial cells (ECs) has been shown to significantly affect intracellular Ca2+ dynamics and NO production, but the effect has not been well quantified. METHODS: We developed a two-dimensional continuum model of an EC integrating shear stress-mediated ATP production, intracellular Ca2+ mobilization, and eNOS activation to investigate the effects of spatial colocalization of plasma membrane eNOS and CCE channels on Ca2+ dynamics and NO production in response to flow-induced shear stress. Our model examines the hypothesis that subcellular colocalization of cellular components can be critical for optimal coupling of NO production to blood flow. RESULTS: Our simulations predict that heterogeneity of CCE can result in formation of microdomains with significantly higher Ca2+ compared to the average cytosolic Ca2+. Ca2+ buffers with lower or no mobility further enhanced Ca2+ gradients relative to mobile buffers. Colocalization of eNOS to CCE channels significantly increased NO production. CONCLUSIONS: Our results provide quantitative understanding for the role of spatial heterogeneity and the compartmentalization of signals in regulation of shear stress-induced NO production.
INTRODUCTION: Colocalization of endothelial nitric oxide synthase (eNOS) and capacitative Ca2+ entry (CCE) channels in microdomains such as cavaeolae in endothelial cells (ECs) has been shown to significantly affect intracellular Ca2+ dynamics and NO production, but the effect has not been well quantified. METHODS: We developed a two-dimensional continuum model of an EC integrating shear stress-mediated ATP production, intracellular Ca2+ mobilization, and eNOS activation to investigate the effects of spatial colocalization of plasma membrane eNOS and CCE channels on Ca2+ dynamics and NO production in response to flow-induced shear stress. Our model examines the hypothesis that subcellular colocalization of cellular components can be critical for optimal coupling of NO production to blood flow. RESULTS: Our simulations predict that heterogeneity of CCE can result in formation of microdomains with significantly higher Ca2+ compared to the average cytosolic Ca2+. Ca2+ buffers with lower or no mobility further enhanced Ca2+ gradients relative to mobile buffers. Colocalization of eNOS to CCE channels significantly increased NO production. CONCLUSIONS: Our results provide quantitative understanding for the role of spatial heterogeneity and the compartmentalization of signals in regulation of shear stress-induced NO production.
Authors: Swapnil K Sonkusare; Adrian D Bonev; Jonathan Ledoux; Wolfgang Liedtke; Michael I Kotlikoff; Thomas J Heppner; David C Hill-Eubanks; Mark T Nelson Journal: Science Date: 2012-05-04 Impact factor: 47.728
Authors: Adam C Straub; Alexander W Lohman; Marie Billaud; Scott R Johnstone; Scott T Dwyer; Monica Y Lee; Pamela Schoppee Bortz; Angela K Best; Linda Columbus; Benjamin Gaston; Brant E Isakson Journal: Nature Date: 2012-10-31 Impact factor: 49.962