Pulsatile shear and Gja5 modulate arterial identity and remodeling events during flow-driven arteriogenesis.
In the developing chicken embryo yolk sac vasculature, the expression of arterial identity genes requires arterial hemodynamic conditions. We hypothesize that arterial flow must provide a unique signal that is relevant for supporting arterial identity gene expression and is absent in veins. We analyzed factors related to flow, pressure and oxygenation in the chicken embryo vitelline vasculature in vivo. The best discrimination between arteries and veins was obtained by calculating the maximal pulsatile increase in shear rate relative to the time-averaged shear rate in the same vessel: the relative pulse slope index (RPSI). RPSI was significantly higher in arteries than veins. Arterial endothelial cells exposed to pulsatile shear in vitro augmented arterial marker expression as compared with exposure to constant shear. The expression of Gja5 correlated with arterial flow patterns: the redistribution of arterial flow provoked by vitelline artery ligation resulted in flow-driven collateral arterial network formation and was associated with increased expression of Gja5. In situ hybridization in normal and ligation embryos confirmed that Gja5 expression is confined to arteries and regulated by flow. In mice, Gja5 (connexin 40) was also expressed in arteries. In the adult, increased flow drives arteriogenesis and the formation of collateral arterial networks in peripheral occlusive diseases. Genetic ablation of Gja5 function in mice resulted in reduced arteriogenesis in two occlusion models. We conclude that pulsatile shear patterns may be central for supporting arterial identity, and that arterial Gja5 expression plays a functional role in flow-driven arteriogenesis.
Buschmann
Ivo
I
Experimental and Clinical Research Center (ECRC) of the Charite and the Max-Delbrueck Center for Molecular Medicine (MDC), D13125 Berlin-Buch, Germany.
Pries
Axel
A
Styp-Rekowska
Beata
B
Hillmeister
Philipp
P
Loufrani
Laurent
L
Henrion
Daniel
D
Shi
Yu
Y
Duelsner
Andre
A
Hoefer
Imo
I
Gatzke
Nora
N
Wang
Haitao
H
Lehmann
Kerstin
K
Ulm
Lena
L
Ritter
Zully
Z
Hauff
Peter
P
Hlushchuk
Ruslan
R
Djonov
Valentin
V
van Veen
Toon
T
le Noble
Ferdinand
F
D000818:Animals; D001011:Aorta / Q000196:embryology / Q000378:metabolism; D001158:Arteries / Q000196:embryology* / Q000648:ultrastructure; D002642:Chick Embryo; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008855:Microscopy, Electron, Scanning; D018919:Neovascularization, Physiologic; D033081:Shear Strength; D000097003:Gap Junction alpha-5 Protein
D017630:Connexins; D000097003:Gap Junction alpha-5 Protein