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RENAL HEMODYNAMICS AND CARDIORENAL INTEGRATION

Integrin-mediated mechanotransduction in renal vascular smooth muscle cells: activation of calcium sparks

Departments of ¹Molecular Pharmacology and Physiology, and ²Physics, University of South Florida, Tampa, Florida; and ³Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland

Submitted 16 January 2007 ; accepted in final form 4 August 2007

Integrins are transmembrane heterodimeric proteins that link extracellular matrix (ECM) to cytoskeleton and have been shown to function as mechanotransducers in nonmuscle cells. Synthetic integrin-binding peptide triggers Ca²⁺ mobilization and contraction in vascular smooth muscle cells (VSMCs) of rat afferent arteriole, indicating that interactions between the ECM and integrins modulate vascular tone. To examine whether integrins transduce extracellular mechanical stress into intracellular Ca²⁺ signaling events in VSMCs, unidirectional mechanical force was applied to freshly isolated renal VSMCs through paramagnetic beads coated with fibronectin (natural ligand of ₅₁-integrin in VSMCs). Pulling of fibronectin-coated beads with an electromagnet triggered Ca²⁺ sparks, followed by global Ca²⁺ mobilization. Paramagnetic beads coated with low-density lipoprotein, whose receptors are not linked to cytoskeleton, were minimally effective in triggering Ca²⁺ sparks and global Ca²⁺ mobilization. Preincubation with ryanodine, cytochalasin-D, or colchicine substantially reduced the occurrence of Ca²⁺ sparks triggered by fibronectin-coated beads. Binding of VSMCs with antibodies specific to the extracellular domains of _5- and ₁-integrins triggered Ca²⁺ sparks simulating the effects of fibronectin-coated beads. Preincubation of microperfused afferent arterioles with ryanodine or integrin-specific binding peptide inhibited pressure-induced myogenic constriction. In conclusion, integrins transduce mechanical force into intracellular Ca²⁺ signaling events in renal VSMCs. Integrin-mediated mechanotransduction is probably involved in myogenic response of afferent arterioles.

myogenic response; paramagnetic bead; fluorescence confocal microscopy

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