ENDOCRINE CONTROL OF FETAL CARDIOVASCULAR DYNAMICS

  • Cheung, Cecilia (PI)

Project: Research project

Project Details

Description

The purposes of the proposed studies are 1) to generate a comprehensive
understanding of the role of the cardiac hormone ANF in the long-term
maintenance of fetal cardiovascular function under normal and stress
conditions, 2) to examine the endocrine and paracrine factors which
regulate the release of ANF under normal and stress conditions, and their
site of action at the cellular and molecular levels, and 3) to explore
the developmental pattern of ANF gene expression in fetal atria and
ventricles, and the effects of stress in altering this pattern of
expression. The stress conditions to be studied are prolonged hypoxia
and volume expansion. The approach taken is to first utilize the whole
animal model to define the long-term cardiovascular and renal effects of
ANF. Secondly, whole animal and cell culture experiments will be used
in combination to delineate the factors which mediate ANF release and
expression. Thirdly, molecular techniques will be used to determine ANF
gene expression. These studies will be carried out in ovine fetuses at
105 to 115 days and 130 to 140 days gestation (term = 145 days) in order
to determine the developmental changes in these regulatory mechanisms.
The cardiovascular variables to be measured are arterial and venous
pressures, heart rate, cardiac output, blood gases and pH, hematocrit and
plasma protein concentration, urine flow rate and urinary excretion of
electrolytes. In the first series of experiments, the effects of a long-
term infusion of ANF on fetal cardiovascular variables will be determined
in chronically catheterized fetuses. The involvement of ANF in returning
arterial pressure, blood volume and urine flow to normal during prolonged
hypoxia and volume loading will be investigated by the use of a specific
antagonist for ANF. The second series of experiments will be carried out
in chronically catheterized fetuses to delineate the effects of
endothelin, norepinephrine and epinephrine in mediating ANF release, and
in cultured fetal atrial cardiocytes to examine the direct effects of
these factors in stimulating ANF secretion and expression of ANF
messenger RNA. The third series of experiments will be carried out in
fetal heart tissues to determine the pattern of expression of ANF
messenger RNA in the atria and ventricles, and the effects of prolonged
hypoxia or volume expansion in altering this expression. We will test
the following hypotheses in the fetus: 1) ANF is an important hormone in
the longterm maintenance of cardiovascular function under normal
conditions and during the stress of hypoxia or volume expansion, 2)
endothelin and the catecholamines are mediators for ANF release, and they
act directly on fetal atrial cardiocytes to enhance ANF secretion and
induce the expression of ANF messenger RNA, and 3) the level of ANF gene
expression in the atria and ventricles of the fetus during the latter
half of gestation can be induced by prolonged stress of hypoxia or volume
expansion. These studies are important because they will expand our
knowledge of the control of the fetal abnormalities in utero and stress
at birth.
StatusFinished
Effective start/end date12/1/845/31/02

Funding

  • National Institutes of Health: $250,293.00
  • National Institutes of Health
  • National Institutes of Health: $247,001.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $181,197.00
  • National Institutes of Health
  • National Institutes of Health: $206,645.00
  • National Institutes of Health
  • National Institutes of Health: $172,499.00
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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