Abstract
Tibial dyschondroplasia (TD) is an intractable poultry problem that is characterized by the appearance of non-vascularized and non-mineralized cartilage masses in tibial growth plates (TGPs). However, the role of angiogenesis inhibition in the occurrence of TD remains unknown. In this study, we found that, compared to low-altitude Arbor Acres chickens (AACs), high-altitude Tibetan chickens showed higher tibial vascular distributions that were accompanied by up-regulation of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor A (VEGFA) and VEGF receptors. These observations provide insights into hypoxia-induced angiogenesis, which may be related to the absence of TD in high-altitude native Tibetan chickens. Importantly, hypoxia experiments also showed that during hypoxia, tibial angiogenesis was enhanced, which was due to pro-angiogenic factor up-regulation (including VEGFA, VEGFR1, VEGFR2, and IL-8), in AACs. Moreover, we observed that thiram-induced TD could strongly inhibit tibial angiogenesis in the hypertrophic zone through coordinated down-regulation of HIF-1α and pro-angiogenic factors, leading to a disruption in the blood supply to the TGP. Taken together, these findings reveal that the occurrence of TD is highly associated with inhibition of tibial angiogenesis through down-regulated expression of HIF-1α, VEGFA and VEGF receptors, which results in suppression of TGP development.
Highlights
Normal development of the bone is very important in meat-type broilers
hypoxia-inducible factor-1α (HIF-1α) is the major regulator of the hypoxia responses, which can activate the downstream genes of vascular endothelial growth factor A (VEGFA) and even the expression of vascular endothelial growth factor (VEGF) receptors (VEGFR1/2), while VEGFA is a master regulator of angiogenesis and appears to be the most selective angiogenic factor acting on endothelial cells[21,22,23,24]
Our study found that the length, growth plate, and growth plate index (T. growth plate width/T. length, μm/mm) of the tibiae were clearly lower in Tibetan chicken (TBC) than in Arbor Acres chickens (AACs) during the experimental period (p < 0.001, p < 0.001, and p < 0.001 respectively; Fig. 1b,f–h)
Summary
Normal development of the bone is very important in meat-type broilers. Abnormal development of the bone (such as tibial dyschondroplasia, rickets, femoral head necrosis, and perosis) can lead to severe economic losses to the poultry industry and directly compromise poultry welfare[1,2,3,4,5]. The invading vasculature triggers the calcified hypertrophic cartilage matrix and formation of the bone marrow cavity and recruits osteoblast and osteoclast precursors that are converted to bone trabecula; eventually, cartilage is replaced by mineralized bone deposits[13,14,15,16,17] This program of tibial development is regulated by a complex molecular mechanism, including the mechanistic target of rapamycin (mTOR) pathway, PI3K/AKT/SMAD1 pathway, hypoxia-inducible factor (HIF)-1α pathway and vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) pathway[15, 18,19,20]. In this study, we employed a thiram-induced TD model, which is commonly used to study the poultry TD model, to investigate the impact of inhibition of angiogenesis-related genes in regulating angiogenesis and its underlying mechanisms
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