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(Circulation Research. 2001;88:925.)
© 2001 American Heart Association, Inc.

Cellular Biology

Lysophosphatidic Acid Positively Regulates the Fluid Flow–Induced Local Ca²⁺ Influx in Bovine Aortic Endothelial Cells

Hisayuki Ohata, Tadahiro Ikeuchi, Aya Kamada, Masayuki Yamamoto, Kazutaka Momose

From the Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.

Correspondence to Hisayuki Ohata, PhD, Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. E-mail ohata{at}pharm.showa-u.ac.jp

Abstract—Using real-time confocal microscopy, we have demonstrated that lysophosphatidic acid (LPA), a bioactive phospholipid existing in plasma, positively regulates fluid flow–induced [Ca²⁺]_i response in fluo 4–loaded, cultured, bovine aortic endothelial cells. The initial increase in [Ca²⁺]_i was localized to a circular area with a diameter of <4 µm and spread concentrically, resulting in a mean global increase in [Ca²⁺]_i. The local increase often occurred in a stepwise manner or repetitively during constant flow. The percentage of cells that responded and the averaged level of increase in [Ca²⁺]_i were dependent on both the concentration of LPA (0.1 to 10 µmol/L) and the flow rate (25 to 250 mm/s). The response was inhibited by removing extracellular Ca²⁺ or by the application of Gd³⁺, an inhibitor of mechanosensitive (MS) channels, but not by thapsigargin, an inhibitor of the endoplasmic reticular Ca²⁺-ATPase. It was also inhibited by 8-bromo-cGMP, and the inhibition was completely reversed by KT5823, an inhibitor of protein kinase G (PKG). These results suggest that the [Ca²⁺]_i response arises from Ca²⁺ influx through Gd³⁺-sensitive MS channels, which are negatively regulated by the activation of PKG. The spatiotemporal properties of the [Ca²⁺]_i response were completely different from those of a Ca²⁺ wave induced by ATP, a Ca²⁺-mobilizing agonist. Therefore, we called the phenomenon Ca²⁺ spots. We conclude that LPA positively regulates fluid flow–induced local and oscillatory [Ca²⁺]_i increase, ie, the Ca²⁺ spots, in endothelial cells via the activation of elementary Ca²⁺ influx through PKG-regulating MS channels. This indicates an important role for LPA as an endogenous factor in fluid flow–induced endothelial function.

Key Words: endothelium • mechanotransduction • Ca²⁺ imaging • ion channels • phospholipids

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