Abstract
AimsAtherosclerosis develops near branches and bends of arteries that are exposed to disturbed blood flow which exerts low wall shear stress (WSS). These mechanical conditions alter endothelial cells (EC) by priming them for inflammation and by inducing turnover. Homeobox (Hox) genes are developmental genes involved in the patterning of embryos along their anterior–posterior and proximal–distal axes. Here we identified Hox genes that are regulated by WSS and investigated their functions in adult arteries.Methods and resultsEC were isolated from inner (low WSS) and outer (high WSS) regions of the porcine aorta and the expression of Hox genes was analysed by quantitative real-time PCR. Several Hox genes (HoxA10, HoxB4, HoxB7, HoxB9, HoxD8, HoxD9) were significantly enriched at the low WSS compared to the high WSS region. Similarly, studies of cultured human umbilical vein EC (HUVEC) or porcine aortic EC revealed that the expression of multiple Hox genes (HoxA10, HoxB9, HoxD8, HoxD9) was enhanced under low (4 dyn/cm2) compared to high (13 dyn/cm2) WSS conditions. Gene silencing studies identified Hox genes (HoxB9, HoxD8, HoxD9) that are positive regulators of inflammatory molecule expression in EC exposed to low WSS, and others (HoxB9, HoxB7, HoxB4) that regulated EC turnover. We subsequently focused on HoxB9 because it was strongly up-regulated by low WSS and, uniquely, was a driver of both inflammation and proliferation. At a mechanistic level, we demonstrate using cultured EC and murine models that bone morphogenic protein 4 (BMP4) is an upstream regulator of HoxB9 which elicits inflammation via induction of numerous inflammatory mediators including TNF and downstream NF-κB activation. Moreover, the BMP4-HoxB9-TNF pathway was potentiated by hypercholesterolaemic conditions.ConclusionsLow WSS induces multiple Hox genes that control the activation state and turnover of EC. Notably, low WSS activates a BMP4-HoxB9-TNF signalling pathway to initiate focal arterial inflammation, thereby demonstrating integration of the BMP and Hox systems in vascular pathophysiology.
Highlights
HOX genes that localize to four clusters in the genome
We subsequently focused on HoxB9 because it was strongly up-regulated by low wall shear stress (WSS) and, uniquely, was a driver of both inflammation and proliferation
(WSS)3,4 which promotes atherogenesis by inducing vascular inflammahanced in the aortic arch which is relatively prone to atherosclerosis tion4–6 and endothelial cell (EC) turnover7,8 coupled to enhanced percompared to the thoracic aorta which is atheroresistant,22 whereas meability to cholesterol-containing lipoproteins
Summary
HOX genes that localize to four clusters in the genome (called HOX A, B, C, and D). They are expressed at distinct regions of the embryo and associated with risk factors that act systemically (e.g. hypercho-act as master regulators of segmental identity and body patterning by aclesterolaemia, smoking, age), atherosclerosis develops preferentially tivating transcriptional programmes that control cell fate decisions.19near branches and bends of arteries.Notably, the expression of several Hox gene varies according to the1,2 Disturbed blood flow at these sites generates low wall shear stress anatomy of the vascular tree. For example, HoxA1 expression is en-(WSS) which promotes atherogenesis by inducing vascular inflamma-hanced in the aortic arch which is relatively prone to atherosclerosis tion and endothelial cell (EC) turnover coupled to enhanced per-compared to the thoracic aorta which is atheroresistant, whereas meability to cholesterol-containing lipoproteins. Low WSS HoxA4 exhibits the opposite pattern. some Hox genes ex-. HOX genes that localize to four clusters in the genome (called HOX A, B, C, and D). They are expressed at distinct regions of the embryo and associated with risk factors that act systemically Act as master regulators of segmental identity and body patterning by aclesterolaemia, smoking, age), atherosclerosis develops preferentially tivating transcriptional programmes that control cell fate decisions.. The expression of several Hox gene varies according to the. 1,2 Disturbed blood flow at these sites generates low wall shear stress anatomy of the vascular tree.. (WSS) which promotes atherogenesis by inducing vascular inflamma-.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
