Clinical Science (2012) 123, 437–444 (Printed in Great Britain)doi:10.1042/CS20110637
Intrauterine growth restriction promotes
vascular remodelling following carotid
artery ligation in rats
Carlos MENENDEZ-CASTRO∗, Nada CORDASIC†, Matthias SCHMID‡,
Fabian FAHLBUSCH∗, Wolfgang RASCHER∗, Kerstin AMANN§, Karl F. HILGERS†
and Andrea HARTNER∗
∗Department of Pediatrics and Adolescent Medicine, University of Erlangen-N¨ urnberg, Erlangen, Germany, †Department of
Nephrology and Hypertension, University of Erlangen-N¨ urnberg, Erlangen, Germany, ‡Department of Medical Informatics,
Biometry and Epidemiology, University of Erlangen-N¨ urnberg, Erlangen, Germany, and §Department of Nephropathology,
University of Erlangen-N¨ urnberg, Erlangen, Germany
Epidemiological studies revealed an association between IUGR (intrauterine growth restriction)
and an increased risk of developing CVDs (cardiovascular diseases), such as atherosclerosis or
vascular remodelling. IUGR was induced in rats by maternal protein restriction during pregnancy
(8% protein diet). To detect possible differences in the development of vascular injury, a model
of carotid artery ligation to induce vascular remodelling was applied in 8-week-old intrauterine-
growth-restricted and control rat offspring. Histological and immunohistochemical analyses were
performed in the ligated and non-ligated carotid arteries 8 weeks after ligation. IUGR alone
neither caused overt histological changes nor significant dedifferentiation of VSMCs (vascular
smooth muscle cells). After carotid artery ligation, however, neointima formation, media thickness
and media/lumen ratio were significantly increased in rats after IUGR compared with controls.
Moreover, dedifferentiation of VSMCs and collagen deposition in the media were more prominent
in ligated carotids from rats after IUGR compared with ligated carotids from control rats. We
conclude that IUGR aggravates atherosclerotic vascular remodelling induced by a second injury
later in life.
Numerous epidemiological and animal studies suggest
that besides the well-known candidates such as arterial
hypertension, diabetes mellitus and hypercholester-
risk factor of atherosclerosis [1,2]. The incidence of
in IUGR patients and IUGR therefore promotes the
development of atherosclerotic lesions at least in an
indirect manner . On the other hand, findings from
an early detectable alteration of vascular structure
and composition and low birth weight [4–7]. These
observations suggest that IUGR may also directly
increase the vascular susceptibility to atherosclerosis,
independent of its effect on classical risk factors.
The quantity of animal models capable of inducing
IUGR reflects the numerous underlying pathomechan-
isms . In this study, the maternal LP (low-protein)
Key words: atherosclerotic lesion, carotid artery ligation, intrauterine growth restriction, maternal protein restriction, vascular
Abbreviations: BP, blood pressure; CTGF, connective tissue growth factor; IUGR, intrauterine growth restriction; LP, low-protein;
NP, normal-protein; PAS, periodate–Schiff; PCNA, proliferating-cell nuclear antigen; VSMC, vascular smooth muscle cell.
Correspondence: Dr Carlos Menendez-Castro, MD (email email@example.com).
C ?The Authors Journal compilation
C ?2012 Biochemical Society
C. Menendez-Castro and others
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Received 8 December 2011/18 April 2012; accepted 23 April 2012
Published as Immediate Publication 23 April 2012, doi:10.1042/CS20110637
C ?The Authors Journal compilation
C ?2012 Biochemical Society