Altered apoptosis pattern during pharyngeal arch artery remodelling is associated with aortic arch malformations in Tgfbeta2 knock-out mice.
OBJECTIVE
The morphogenetic process underlying the remodelling of the embryonic mammalian pharyngeal arch artery system is unknown. Within this process, the right sixth, carotid ducts and the distal part of the dorsal aorta (right alpha-segment) regress. In order to unravel the underlying mechanism we studied the role of apoptosis in the normal regression of pharyngeal arch artery segments and in a mouse model that develops aortic arch malformations.


METHODS
Normal remodelling was studied in wild-type Swiss (CPBS) and altered remodelling in the Tgfbeta2-/- compared to the Tgfbeta2+/+ (Swiss/Bl6) strain using immunohistochemistry and morphometric analysis.


RESULTS
During normal remodelling, apoptosis occurs in the mesenchyme surrounding pharyngeal arch arteries before regression starts. With the onset of regression, apoptosis spreads from the mesenchyme to the media. Morphometric evaluation confirms the increase in apoptosis in the actin-positive media of the disappearing segments. In Tgfbeta2-/-, aberrant apoptosis was found in both fourth arch arteries, whereas the right dorsal aorta lacks apoptosis associated with normal regression. Fourth arch hypoplasia is the main arch abnormality. In the most severe case, the fourth arch is interrupted and the right dorsal aorta alpha-segment persists, giving rise to aortic arch interruption type-B and an aberrant right subclavian artery.


CONCLUSIONS
We have shown for the first time that specific vascular apoptosis patterns accompany normal regression and that the incidence of apoptosis is selectively altered in the case of arch artery abnormalities in Tgfbeta2 knock-out mice.
Molin
Daniël G M
DG
Department of Anatomy and Embryology, Leiden University Medical Centre, P.O. Box 9602, 2300 RC, Leiden, The Netherlands.
DeRuiter
Marco C
MC
Wisse
Lambertus J
LJ
Azhar
Mohamad
M
Doetschman
Thomas
T
Poelmann
Robert E
RE
Gittenberger-de Groot
Adriana C
AC
D000818:Animals; D001013:Aorta, Thoracic / Q000002:abnormalities* / Q000196:embryology / Q000473:pathology; D017209:Apoptosis; D001934:Branchial Region / Q000166:cytology / Q000196:embryology* / Q000473:pathology; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000502:physiology*; D053781:Transforming Growth Factor beta2
D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2