Large epidemiological studies and animal studies have indicated a clear association of adverse intrauterine environment with an increased incidence of low birth weight, perinatal mortality, and cardiovascular disease in later adult life. In humans, one of the most common stresses in utero is hypoxia. The goal of this project is to test the hypothesis that fetal hypoxia causes reprogramming of MMPs and TIMPs expression patterns and activities leading to aberrant brain and heart development in the fetuses and neonates. In the first part of project, we tested the hypothesis that maternal hypoxia increases the activity of MMPs and decreases the expression of TIMPs in the brain of neonatal rats. This was accomplished by using a rat model. Time-dated pregnant rats were divided between normoxic and hypoxia (10.5% O2 on days 15-21 of gestation). Our studies demonstrated that fetal hypoxia impaired the proteolytic balance by increasing the activity of MMPs and decreasing the expression of TIMPs in the brain of neonatal rats and that unopposed extracellular matrix degradation was likely to contribute to the brain injury and growth restriction observed in the present study. The second part of project focused on the effect of fetal hypoxia on heart development. We demonstrated that maternal hypoxia during gestation altered MMPs and TIMPs expression patterns in the developing heart and resulted in the abnormal cardiac growth pattern and cardiomyocyte proliferation with the aberrant content of fibrillar collagen network in fetal and neonatal hearts. We further explored the direct effect of hypoxia on cardiomyocyte proliferation by using intact fetal hearts ex vivo model and H9c2 cells in vitro model. Our collective observations indicated an inhibitory effect on cell proliferation in the developing hearts following hypoxia, which can be mediated by upregulation of TIMP-4. These findings provide a mechanistic understanding worth of investigation in humans in fetal origins of neurovascular and cardiovascular disease caused by intrauterine adverse environment.

LLU Discipline



Basic Sciences


School of Medicine

First Advisor

Zhang, Lubo

Second Advisor

Blood, Arlin B.

Third Advisor

Buchholz, John N.

Fourth Advisor

Ducsay, Charles A.

Fifth Advisor

Xiao, Daliao

Degree Name

Doctor of Philosophy (PhD)

Degree Level


Year Degree Awarded

January 2012

Date (Title Page)




Library of Congress/MESH Subject Headings

Cardiovascular Disease; Hypoxia-Ischemia, Brain; Fetal Hypoxia; Fetal Heart; Fetal Development

Subject - Local

Birth weight; Perinatal mortality; Adverse Intrauterine Environment; MMP; TIMP; Matrix Metalloproteinase; Tissue Inhibitors of Metalloproteinase



Page Count

139 p.

Digital Format


Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.


Loma Linda University Electronic Theses & Dissertations

Collection Website



Loma Linda University. Del E. Webb Memorial Library. University Archives