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Endothelial Cell Calcium Signaling R...

Weber, Evan William.

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Endothelial Cell Calcium Signaling Regulates Leukocyte Transendothelial Migration During the Inflammatory Response.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Endothelial Cell Calcium Signaling Regulates Leukocyte Transendothelial Migration During the Inflammatory Response./
作者:	Weber, Evan William.
面頁冊數:	209 p.
附註:	Source: Dissertation Abstracts International, Volume: 77-08(E), Section: B.
Contained By:	Dissertation Abstracts International77-08B(E).
標題:	Immunology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10043993
ISBN:	9781339554464

Endothelial Cell Calcium Signaling Regulates Leukocyte Transendothelial Migration During the Inflammatory Response.
Weber, Evan William.

Endothelial Cell Calcium Signaling Regulates Leukocyte Transendothelial Migration During the Inflammatory Response. - 209 p.

Source: Dissertation Abstracts International, Volume: 77-08(E), Section: B.

Thesis (Ph.D.)--Northwestern University, 2016.

During the inflammatory response, leukocytes are recruited into the affected tissue through a series of tightly regulated and mechanistically distinct interactions with the vascular endothelium. The final step, in which leukocytes traverse the endothelium by squeezing between two tightly opposed endothelial cells, is called transendothelial migration (TEM). Homophilic interactions between leukocyte and endothelial PECAM and a transient increase in endothelial cytosolic free calcium ion concentration ([Ca2+]i) are required for TEM. However, the source of [Ca2+]i, which calcium channels are involved, and whether a functional relationship exists between PECAM and [Ca2+]i are not known. In the present study, we show that buffering endothelial [Ca2+]i does not affect leukocyte adhesion or locomotion, but selectively blocks TEM, suggesting a role for [Ca2+]i specifically for this step. TRPC6, a Ca2+ channel expressed in endothelial cells, co-localizes with PECAM to surround leukocytes during TEM and clusters when endothelial PECAM is engaged. Consistent with this finding, PECAM engagement activates VEGFR2 and PLC?1, both of which are known to act upstream of TRPC6 in other physiological contexts. Importantly, endothelial TRPC6 is functionally critical for leukocyte TEM. Expression of dominant-negative TRPC6 or shRNA knockdown in endothelial cells apically arrests neutrophils, similar to when PECAM is blocked. Selectively activating endothelial TRPC6 rescues TEM in anti-PECAM-arrested neutrophils, indicating that TRPC6 functions downstream of PECAM. Furthermore, endothelial TRPC6 is required for trafficking of LBRC membrane, which facilitates TEM. Finally, mice lacking TRPC6 in the non-myeloid compartment (i.e., endothelium) exhibit a profound defect in neutrophil TEM with no effect on leukocyte trafficking. Thus, TRPC6 is the endothelial Ca2+ channel that regulates TEM. Although some investigators have characterized endothelial [Ca2+]i during TEM in vitro, no one has studied [Ca2+]i during this process in vivo. In mice expressing the calcium biosensor GCaMP3 specifically in the endothelium, transmigrating neutrophils elicit local endothelial [Ca2+]i in the area surrounding the transmigratory pore as visualized by high resolution intravital microscopy. Local [Ca2+]i is sustained for the entire duration of neutrophil TEM. Collectively, these data highlight a novel and critical role for endothelial [Ca2+]i and TRPC6 during the inflammatory response and provide new insight into PECAM-mediated signaling.

ISBN: 9781339554464Subjects--Topical Terms:

611031
Immunology.

Endothelial Cell Calcium Signaling Regulates Leukocyte Transendothelial Migration During the Inflammatory Response.
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