Paper of the Month - July/August 2014

Uchida C, Haas TL. Endothelial cell TIMP-1 is upregulated by shear stress via Sp-1 and the TGFb signaling pathways. Biochem Cell Biol. 92(1):77-83, 2014.


Endothelial cells, which form the inner lining of all blood vessels, are constantly exposed to the frictional force of flowing blood, which is known as shear stress. This force, which is exerted parallel to the surface of the endothelial cells, has the potential to damage cells and in extreme, rip endothelial cells away from their location in the vessel wall. Endothelial cells have developed numerous adaptive mechanisms that allow them to resist the damaging influence of shear stress.  One such mechanism is the production of protease inhibitors that prevent the excessive degradation of the matrix proteins to which endothelial cells attach.  While it is recognized that shear stress increases the production of protease inhibitors, the cellular signaling mechanisms that control this response are not known. In this study, we investigated the regulatory mechanisms the control the production of the protease inhibitor, tissue inhibitor of matrix metalloproteinase -1 (TIMP-1). Using cultured endothelial cells exposed to a defined level of shear stress for varying amounts of time, we observed a biphasic increase in TIMP-1 protein, at 2 and 24 h of shear stress exposure. We demonstrated that the early increase in TIMP-1 protein required the transcription factor Sp1. We also found that production of the growth factor transforming growth factor beta (TGFb) was increased by shear stress. We showed that inhibition of TGFb signaling, either by blocking the TGFb receptor, or by siRNA inhibition of the TGFb-specific transcription factors SMAD2,3, prevented the shear stress induced increase in TIMP-1 after long term (24 h) shear stress exposure. These results suggest that both acute and chronic elevations in shear stress stimulate signals to maintain blood vessel integrity through increasing TIMP-1 production, and that the TGFb signaling pathway is an essential component of this response. It is possible that disruptions in this normal signaling pathway may contribute to the development of vascular diseases.

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Previous Papers of the Month:

2014

Month

Investigator(s)

January
Dr. Haas
February
Dr. Hamadeh
March
Dr. Hood
April
Dr. Adegoke
May
Dr. Scimè
June
Dr. McDermott
July/August
Dr. Haas
September
October
November
December

2013

Month

Investigator(s)

January
Dr. Hood
February
Dr. Haas
March
Dr. Birot
April
Dr. Hamadeh
May
Dr. McDermott
June
Dr. Riddell
July
Dr. Perry
August/September
Dr. Ceddia
October
Dr. Kuk
November
Dr. Gage
December
Dr. Hawke

2012

Month

Investigator(s)

January
Dr. Kuk
February
Dr. Hamadeh
March
Dr. Hood
April/May
Dr. Ceddia
June
Dr. Hawke
July
Dr. McDermott
August/September
Dr. Riddell
October
Dr. Kuk
November
Dr. Adegoke
December
Dr. Hamadeh

2011

Month

Investigator(s)

January
Dr. Scimè
February
Dr. Coe
Dr. Haas
March
Dr. Riddell
April
Dr. Birot
May
Dr. Hood
June
Dr. Hood
July
Dr. Adegoke
August
Dr. Riddell
September
Dr. Coe
October
Dr. Hamadeh
November
Dr. Gage
Dr. Haas
December
Dr. Riddell/Dr. Adegoke
Dr. McDermott

2010

Month

Investigator(s)

January
Dr. Scimè
February
Dr. Haas
March
Dr. McDermott
April/May
Dr. Coe
June
Dr. Hamadeh
July
Dr. Riddell
August
Dr. Ceddia
September
Dr. Gage
October/November
Dr. Hood

2009

Month

Investigator(s)

December
Dr. Hood