Data_Sheet_2_Nxhl Controls Angiogenesis by Targeting VE-PTP Through Interaction With Nucleolin.zip

Precise regulation of angiogenesis is required for organ development, wound repair, and tumor progression. Here, we identified a novel gene, nxhl (New XingHuo light), that is conserved in vertebrates and that plays a crucial role in vascular integrity and angiogenesis. Bioinformatic analysis uncovered its essential roles in development based on co-expression with several key developmental genes. Knockdown of nxhl in zebrafish causes global and pericardial edema, loss of blood circulation, and vascular defects characterized by both reduced vascularization in intersegmental vessels and decreased sprouting in the caudal vein plexus. The nxhl gene also affects human endothelial cell behavior in vitro. We found that nxhl functions in part by targeting VE-PTP through interaction with NCL (nucleolin). Loss of ptprb (a VE-PTP ortholo) in zebrafish resulted in defects similar to nxhl knockdown. Moreover, nxhl deficiency attenuates tumor invasion and proteins (including VE-PTP and NCL) associated with angiogenesis and EMT. These findings illustrate that nxhl can regulate angiogenesis via a novel nxhl–NCL–VE-PTP axis, providing a new therapeutic target for modulating vascular formation and function, especially for cancer treatment.

器官发育、伤口修复及肿瘤进展均需对血管生成（angiogenesis）进行精准调控。本研究鉴定出一个在脊椎动物中保守的新型基因nxhl（New XingHuo light），其在维持血管完整性与调控血管生成过程中发挥关键作用。生物信息学分析显示，该基因与多个核心发育调控基因共表达，提示其在个体发育中具有不可或缺的功能。在斑马鱼模型中敲低nxhl会引发全身性及心包水肿、血液循环丧失，并出现血管缺陷：具体表现为节间血管的血管形成减少，以及尾静脉丛的出芽生成受阻。nxhl基因在体外亦可影响人内皮细胞的生物学行为。我们发现，nxhl主要通过与核仁素（nucleolin，NCL）相互作用，靶向血管内皮蛋白酪氨酸磷酸酶（VE-PTP）发挥功能。在斑马鱼中敲低ptprb（VE-PTP同源基因）所引发的发育缺陷与nxhl敲低后的表型相似。此外，nxhl缺失会减弱肿瘤侵袭能力，并降低与血管生成及上皮间质转化（EMT）相关的蛋白（包括VE-PTP与NCL）的表达水平。上述研究结果表明，nxhl可通过一条全新的nxhl-NCL-VE-PTP信号轴调控血管生成，为调控血管形成与血管功能提供了新的治疗靶点，尤其可为肿瘤治疗提供新的干预方向。