| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Institut für Physiologie, Universität Hamburg, D-20246 Hamburg, Germany
THE TRANSITION FROM THE FETAL
circulation to isolated extrauterine life marks the most dramatic
challenge to an individual's cardiovascular system. Even though the
fundamental peculiarities of the fetal circulation have been discovered
in the 19th century already, many mechanisms playing important roles in
the late-gestational and perinatal fetal circulation remain poorly
understood. This is reflected by the large number of articles dealing
with such unsolved problems that have been published recently in the
American Journal of Physiology-Regulatory, Integrative and
Comparative Physiology. These studies address the maintenance of a
high pulmonary vascular resistance and low pulmonary blood flow before
birth (12), regulation of vascular tone of the fetal
ductus arteriosus (15, 29), specific responses to hypoxia
and hypoxemia (1, 9, 10, 30), programming of postnatal
cardiovascular development by maternal undernutrition
(11), and cardiovascular responses to pharmacological
treatment (6, 24, 28).
Particular attention has been paid to time-dependent changes of local
vascular tone. Given its constantly evolving structure, the presence of
strongly time-dependent functional changes in the fetal circulation
does not seem very surprising. Nevertheless, many of these changes have
not yet been well described and are only beginning to become unraveled.
For example, constriction of fetal ovine cerebral arteries induced by
norepinephrine is, in contrast to adult vessels, independent from
intracellular Ca2+ release, but nearly entirely relies on
Ca2+ influx from the extracellular space through L-type
Ca2+ channels (19). Correspondingly, vascular
tone in these fetal vessels appears to be tightly regulated by
K+ channels via changes in membrane potential
(18). Fetal cerebral arteries also express much lower
levels of the Ca2+-independent isoform protein kinase
C- Another focus of recent interest addresses the developmental roles of
ANG II and nitric oxide (5, 21, 25). The renin-angiotensin system is activated in both the maternal and fetal circulation. Elevated levels of ANG II are possibly detrimental to an adequate perfusion of critical organs, including the maternal uterus and the
fetal kidney. Cox and co-workers (5) showed, by comparing systemic and local intra-arterial infusions of ANG II in sheep, that
uterine vascular responses to ANG II are markedly attenuated during
pregnancy. In the developing kidney, excessive vasoconstriction induced
by ANG II appears to be counterbalanced by nitric oxide. Renal
vasodilator effects of nitric oxide are well established in the adult
(4, 16, 17, 22, 31). The precise source of the enhanced
local release of nitric oxide in the postnatal kidney is not clear yet;
however, both renal nitric oxide synthase I and III mRNA and protein
are expressed at high levels during the first days after birth
(26, 27).
The vast majority (>80%) of the studies described above have been
performed in sheep, which may be rightly named the model organism for
the study of fetal and perinatal cardiovascular development. Because of
a long reproduction time and a lack of genomic information, however,
sheep studies are less useful for the deciphering of the developmental
function of single genes or complex gene pathways. The most promising
model organisms for the study of these latter questions are the mouse
and the zebrafish (Danio rerio). The technique of homologous
recombination to induce mutations has produced an increasingly growing
number of mice carrying targeted gene mutations. Several studies
investigating the normal cardiovascular physiology of the mouse have
recently appeared in this journal (13, 14, 23). Most
notably, Porter and Rivkees (23) studied the ontogeny of
humoral heart rate regulation in cultured murine embryos from postcoital day (PC) 8 onward. As early as
PC 8, immediately after completion of cardiogenesis, heart
rate is significantly altered via A1 adenosine-receptor
activation and shortly thereafter by adrenergic receptor stimulation.
In contrast, responsiveness to acetylcholine develops only after
PC 13, even though muscarinic M2-receptor mRNA
expression was detected by PC 11. This suggests that
coupling of muscarinic M2 receptors to the intracellular signaling cascade is also developmentally regulated. These findings emphasize the importance of local control mechanisms of cardiac function during embryogenesis.
The zebrafish may gain even more importance than the mouse. With regard
to developmental studies aiming to uncover genetic pathways important
for the genesis of the cardiovascular system, the zebrafish has two
advantages: applicability of large-scale mutagenesis screens and its
transparency. Thus genetic alterations can be easily induced and easily
detected. The power of this experimental system was described in detail
in an invited review appearing last month in this journal (3).
The usefulness of this model organism to generate insights into the
relationship between embryonic cardiovascular structure and function
was recently demonstrated by Fritsche and associates (8).
Using a video microscopic technique, these authors could demonstrate
that before peripheral vessels are functionally innervated they are
regulated by an interplay of local factors, including nitric oxide and
catecholamines. Future studies will link these physiological processes
to genetic pathways.
ARTICLE
TOP
ARTICLE
REFERENCES
, which mediates Ca2+-independent contraction of
smooth muscle (20). These observations suggest
considerable developmental changes in pharmacomechanical and
electromechanical coupling. Similarly, endothelium-dependent responses
of isolated resistance arteries greatly vary during the final third of
gestation (7). These responses appear to be agonist
specific and differ between individual vascular beds. This makes
extensions from findings in one vascular bed to another very difficult,
but it may also provide clues to hitherto unrecognized physiological
functions. An example to support such a reasoning may be the finding
that smooth muscle cells from the ovine bladder, which is already
functional early in the midtrimester, undergo a more rapid maturation
of the contractile protein phenotype than aortic smooth muscle cells
(2).
| |
FOOTNOTES |
|---|
Address for reprint requests and other correspondence: H. Ehmke, Institut für Physiologie, Universität Hamburg, Martinistrasse 52, D-20246 Hamburg, Germany (E-mail: ehmke{at}uke.uni-hamburg.de).
10.1152/ajpregu.00599.2001
| |
REFERENCES |
|---|
|
TOP
ARTICLE
REFERENCES
|
|---|
1.
Angeles, DM,
Williams J,
Purdy RE,
Zhang L,
and
Pearce WJ.
Effects of maturation and acute hypoxia on receptor-IP3 coupling in ovine common carotid arteries.
Am J Physiol Regulatory Integrative Comp Physiol
280:
R410-R417,
2001
2.
Arens, YH,
Rosenfeld CR,
and
Kamm KE.
Maturational differences between vascular and bladder smooth muscle during ovine development.
Am J Physiol Regulatory Integrative Comp Physiol
278:
R1305-R1313,
2000
3.
Briggs, JP.
The zebrafish: a new model organism for integrative physiology.
Am J Physiol Regulatory Integrative Comp Physiol
282:
R3-R9,
2002
4.
Cases, A,
Haas J,
Burnett JC,
and
Romero JC.
Hemodynamic and renal effects of acute and progressive nitric oxide synthesis inhibition in anesthetized dogs.
Am J Physiol Regulatory Integrative Comp Physiol
280:
R143-R148,
2001
5.
Cox, BE,
Williams CE,
and
Rosenfeld CR.
Angiotensin II indirectly vasoconstricts the ovine uterine circulation.
Am J Physiol Regulatory Integrative Comp Physiol
278:
R337-R344,
2000
6.
Docherty, CC,
Kalmar-Nagy J,
Engelen M,
Koenen SV,
Nijland M,
Kuc RE,
Davenport AP,
and
Nathanielsz PW.
Effect of in vivo fetal infusion of dexamethasone at 0.75 GA on fetal ovine resistance artery responses to ET-1.
Am J Physiol Regulatory Integrative Comp Physiol
281:
R261-R268,
2001
7.
Docherty, CC,
Kalmar-Nagy J,
Engelen M,
and
Nathanielsz PW.
Development of fetal vascular responses to endothelin-1 and acetylcholine in the sheep.
Am J Physiol Regulatory Integrative Comp Physiol
280:
R554-R562,
2001
8.
Fritsche, R,
Schwerte T,
and
Pelster B.
Nitric oxide and vascular reactivity in developing zebrafish, Danio rerio.
Am J Physiol Regulatory Integrative Comp Physiol
279:
R2200-R2207,
2000
9.
Giussani, DA,
Gardner DS,
Cox DT,
and
Fletcher AJ.
Purinergic contribution to circulatory, metabolic, and adrenergic responses to acute hypoxemia in fetal sheep.
Am J Physiol Regulatory Integrative Comp Physiol
280:
R678-R685,
2001
10.
Harris, AP,
Helou S,
Gleason CA,
Traystman RJ,
and
Koehler RC.
Fetal cerebral and peripheral circulatory responses to hypoxia after nitric oxide synthase inhibition.
Am J Physiol Regulatory Integrative Comp Physiol
281:
R381-R390,
2001
11.
Hawkins, P,
Steyn C,
Ozaki T,
Saito T,
Noakes DE,
and
Hanson MA.
Effect of maternal undernutrition in early gestation on ovine fetal blood pressure and cardiovascular reflexes.
Am J Physiol Regulatory Integrative Comp Physiol
279:
R340-R348,
2000
12.
Jaillard, S,
Houfflin-Debarge V,
Riou Y,
Rakza T,
Klosowski S,
Lequien P,
and
Storme L.
Effects of catecholamines on the pulmonary circulation in the ovine fetus.
Am J Physiol Regulatory Integrative Comp Physiol
281:
R607-R614,
2001
13.
Janssen, BJ,
Leenders PJ,
and
Smits JF.
Short-term and long-term blood pressure and heart rate variability in the mouse.
Am J Physiol Regulatory Integrative Comp Physiol
278:
R215-R225,
2000
14.
Just, A,
Faulhaber J,
and
Ehmke H.
Autonomic cardiovascular control in conscious mice.
Am J Physiol Regulatory Integrative Comp Physiol
279:
R2214-R2221,
2000
15.
Kajino, H,
Chen YQ,
Seidner SR,
Waleh N,
Mauray F,
Roman C,
Chemtob S,
Koch CJ,
and
Clyman RI.
Factors that increase the contractile tone of the ductus arteriosus also regulate its anatomic remodeling.
Am J Physiol Regulatory Integrative Comp Physiol
281:
R291-R301,
2001
16.
Kakoki, M,
Zou AP,
and
Mattson DL.
The influence of nitric oxide synthase 1 on blood flow and interstitial nitric oxide in the kidney.
Am J Physiol Regulatory Integrative Comp Physiol
281:
R91-R97,
2001
17.
Llinás, MT,
Rodríguez F,
Moreno C,
and
Salazar FJ.
Role of cyclooxygenase-2-derived metabolites and nitric oxide in regulating renal function.
Am J Physiol Regulatory Integrative Comp Physiol
279:
R1641-R1646,
2000
18.
Long, W,
Zhang L,
and
Longo LD.
Cerebral artery KATP- and KCa-channel activity and contractility: changes with development.
Am J Physiol Regulatory Integrative Comp Physiol
279:
R2004-R2014,
2000
19.
Long, W,
Zhang L,
and
Longo LD.
Cerebral artery sarcoplasmic reticulum Ca2+ stores and contractility: changes with development.
Am J Physiol Regulatory Integrative Comp Physiol
279:
R860-R873,
2000
20.
Longo, LD,
Zhao Y,
Long W,
Miguel C,
Windemuth RS,
Cantwell AM,
Nanyonga AT,
Saito T,
and
Zhang L.
Dual role of PKC in modulating pharmacomechanical coupling in fetal and adult cerebral arteries.
Am J Physiol Regulatory Integrative Comp Physiol
279:
R1419-R1429,
2000
21.
Moritz, K,
Koukoulas I,
Albiston A,
and
Wintour EM.
Angiotensin II infusion to the midgestation ovine fetus: effects on the fetal kidney.
Am J Physiol Regulatory Integrative Comp Physiol
279:
R1290-R1297,
2000
22.
Murphy, JG,
Fleming JB,
Cockrell KL,
Granger JP,
and
Khalil RA.
[Ca2+]i signaling in renal arterial smooth muscle cells of pregnant rat is enhanced during inhibition of NOS.
Am J Physiol Regulatory Integrative Comp Physiol
280:
R87-R99,
2001
23.
Porter, GA, Jr,
and
Rivkees SA.
Ontogeny of humoral heart rate regulation in the embryonic mouse.
Am J Physiol Regulatory Integrative Comp Physiol
281:
R401-R407,
2001
24.
Segar, JL,
Bedell KA,
and
Smith OJ.
Glucocorticoid modulation of cardiovascular and autonomic function in preterm lambs: role of ANG II.
Am J Physiol Regulatory Integrative Comp Physiol
280:
R646-R654,
2001
25.
Smolich, JJ.
NO supports right ventricular flow dominance and whole body O2 utilization in midgestation fetal lambs.
Am J Physiol Regulatory Integrative Comp Physiol
280:
R1016-R1022,
2001
26.
Solhaug, MJ,
Dong XQ,
Adelman RD,
and
Dong KW.
Ontogeny of neuronal nitric oxide synthase, NOS I, in the developing porcine kidney.
Am J Physiol Regulatory Integrative Comp Physiol
278:
R1453-R1459,
2000
27.
Solhaug, MJ,
Kullaprawithaya U,
Dong XQ,
and
Dong KW.
Expression of endothelial nitric oxide synthase in the postnatal developing porcine kidney.
Am J Physiol Regulatory Integrative Comp Physiol
280:
R1269-R1275,
2001
28.
Stonestreet, BS,
Sadowska GB,
McKnight AJ,
Patlak C,
and
Petersson KH.
Exogenous and endogenous corticosteroids modulate blood-brain barrier development in the ovine fetus.
Am J Physiol Regulatory Integrative Comp Physiol
279:
R468-R477,
2000
29.
Takahashi, Y,
Roman C,
Chemtob S,
Tse MM,
Lin E,
Heymann MA,
and
Clyman RI.
Cyclooxygenase-2 inhibitors constrict the fetal lamb ductus arteriosus both in vitro and in vivo.
Am J Physiol Regulatory Integrative Comp Physiol
278:
R1496-R1505,
2000
30.
Thompson, LP,
Aguan K,
Pinkas G,
and
Weiner CP.
Chronic hypoxia increases the NO contribution of acetylcholine vasodilation of the fetal guinea pig heart.
Am J Physiol Regulatory Integrative Comp Physiol
279:
R1813-R1820,
2000
31.
Zou, AP,
and
Cowley AW.
2-Adrenergic receptor-mediated increase in NO production buffers renal medullary vasoconstriction.
Am J Physiol Regulatory Integrative Comp Physiol
279:
R769-R777,
2000
This article has been cited by other articles:
|
|
 |
|
  J. M Bishai, A. B Blood, C. J Hunter, L. D Longo, and G. G Power Fetal lamb cerebral blood flow (CBF) and oxygen tensions during hypoxia: a comparison of laser Doppler and microsphere measurements of CBF J. Physiol., February 1, 2003; 546(3): 869 - 878. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ruijtenbeek, J. G. R. De Mey, C. E. Blanco ;, and H. Ehmke The Chicken Embryo in Developmental Physiology of the Cardiovascular System: A Traditional Model with New Possibilities Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2002; 283(2): R549 - R551. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
