Thrombin Induces Inositol Trisphosphate–Mediated Spatially Extensive Responses in Lung Microvessels

Rachel Escue, Kathirvel Kandasamy, Kaushik Parthasarathi

Research output: Contribution to journalArticle

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Abstract

Activation of plasma membrane receptors initiates compartmentalized second messenger signaling. Whether this compartmentalization facilitates the preferential intercellular diffusion of specific second messengers is unclear. Toward this, the receptor-mediated agonist, thrombin, was instilled into microvessels in a restricted region of isolated blood-perfused mouse lungs. Subsequently, the thrombin-induced increase in endothelial F-actin was determined using confocal fluorescence microscopy. Increased F-actin was evident in microvessels directly treated with thrombin and in those located in adjoining thrombin-free regions. This increase was abrogated by inhibiting inositol trisphosphate–mediated calcium release with Xestospongin C (XeC). XeC also inhibited the thrombin-induced increase in the amplitude of endothelial cytosolic Ca2+ oscillations. Instillation of thrombin and XeC into adjacent restricted regions increased F-actin in microvessels in the thrombin-treated and adjacent regions but not in those in the XeC-treated region. Thus, inositol trisphosphate, and not calcium, diffused interendothelially to the spatially remote thrombin-free microvessels. Thus, activation of plasma membrane receptors increased the ambit of inflammatory responses via a second messenger different from that used by stimuli that induce cell-wide increases in second messengers. Thrombin however failed to induce the spatially extensive response in microvessels of mice lacking endothelial connexin43, suggesting a role for connexin43 gap junctions. Compartmental second messenger signaling and interendothelial communication define the specific second messenger involved in exacerbating proinflammatory responses to receptor-mediated agonists.

Original languageEnglish (US)
Pages (from-to)921-935
Number of pages15
JournalAmerican Journal of Pathology
Volume187
Issue number4
DOIs
StatePublished - Apr 1 2017

Fingerprint

Inositol
Microvessels
Thrombin
Lung
Second Messenger Systems
Actins
Cell Membrane
Calcium
Connexin 43
Gap Junctions
Fluorescence Microscopy
Confocal Microscopy
Communication
xestospongin C

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Thrombin Induces Inositol Trisphosphate–Mediated Spatially Extensive Responses in Lung Microvessels. / Escue, Rachel; Kandasamy, Kathirvel; Parthasarathi, Kaushik.

In: American Journal of Pathology, Vol. 187, No. 4, 01.04.2017, p. 921-935.

Research output: Contribution to journalArticle

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