Prolylcarboxypeptidase protects from vascular dysfunction and promotes vascular repair

Prolylcarboxypeptidase (PRCP) is a cell surface protease that degrades peptides (including angiotensin II, des-Arg9-bradykinin and alpha-melanocyte stimulating hormone) and activates plasma prekallikrein. The enzyme is highly expressed by endothelial cells where it activates prekallikrein to liberate the vasoactive peptide bradykinin. The following studies characterize the vascular phenotype of the PRCP-deficient (PRCPgt/gt) mouse. Compared to wildtype animals, PRCPgt/gt are hypertensive and demonstrate faster times to induced arterial thrombotic occlusion. PRCPgt/gt have increased levels of vascular reactive oxygen species (ROS) and the hypertensive, prothrombotic phenotypes are corrected by oral antioxidant treatment. The vascular dysfunction induced by PRCP depletion was observed in vitro by siRNA treatment of endothelial cells. Additionally, PRCPgt/gt mice show signs of defective angiogenesis and vascular repair. The animals have decreased presence of vessels in sub-cutaneous injections of matrigel and decreased endothelial sprouting from excised aortic segments. Full thickness skin wounds from PRCPgt/gt heal slower than wildtype mice at the visual level and have decreased invasive blood vessel repair. PRCPgt/gt exhibit defective repair of large vessels as demonstrated by slow recovery from hind limb ischemia and thickened neo-intima formation following wire injury of the femoral artery. In sum, this work suggests PRCP protects from the pathological manifestations of vascular dysfunction and promotes angiogenesis and large vessel repair.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Pathology

Grantor dc:publisher

Case Western Reserve University School of Graduate Studies

Year dc:date

2013

Author dc:creator

• Adams, Gregory Nicholas

Contributors dc:contributor

• Schmaier, Alvin
• McCrae, Keith

• Biomedical Research
• Pathology
• hypertension
• thrombosis
• reactive oxygen species
• ROS
• endothelial
• angiogenesis

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=case1346973249

OAI identifier oai:identifier

oai:etd.ohiolink.edu:case1346973249