The cervix uteri is characterized by a high content of collagen. During most of gestation its rigidity ensures retention of the conceptus. In late pregnancy the cervix ripens, a process characterized by a loosening of the fibrillar collagen network, which precedes disintegration of collagen fibers during cervical dilatation. An influx of polymorphonuclear leukocytes (PMN) to the cervical stroma accompanies fibril disintegration; numerous studies implicate PMN mediated proteolysis in cervical remodeling. The constituents of the cervical stroma, their individual role in matrix stability and cohesion, and their changes during cervical ripening and dilation are poorly understood. We hypothesize that Fibril Associated Collagen with interrupted Triple-Helices (FACIT) type XIV, which we show is abundant in the ovine cervix, plays a central role in conferring matrix cohesion. Our preliminary investigations demonstrate that type XIV collagen is proteolyzed at parturition. In vitro removal of this FACIT from ovine cervical tissue strips dramatically alters biomechanical tissue parameters. We further hypothesize that this proteolysis is dependent upon collagenases secreted from PMN. To test our hypotheses, we first propose to characterize fibrillar and fibril-associated components of the cervical stroma that confer matrix stability and cohesion in the pregnant ovine cervix and to elucidate the expression pattern and cellular origin of these molecules. Then, the impact of selective removal of specific matrix molecules on cervical distensibility will be tested. Finally, we propose to investigate the role of leukocyte collagenases in the proteolysis of type XIV collagen during cervical dilatation. In women, an untimely remodeling process of the cervical extracellular matrix can either lead to a prematurely ripened cervix or an incompliant cervix at term. Moreover, labor induced in the face of an unfavorable cervix can compromise both mother and child. A better understanding of the physiological processes which direct cervical ripening should guide innovative therapy targeting these critical events of parturition.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HD033513-03
Application #
2857462
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Catz, Charlotte S
Project Start
1997-01-01
Project End
1999-07-31
Budget Start
1999-01-01
Budget End
1999-07-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Magee-Women's Hospital of Upmc
Department
Type
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213