Dendritic arborization is critical for the establishment and maintenance of precise neural circuits. Vascular endothelial growth factor D (VEGF-D), well-characterized as a “lymphangiogenic” growth factor, reportedly maintains dendritic arborization and synaptic strength in the hippocampus of adult mice through VEGF receptor (VEGFR-3) signaling. Here, we investigated the effect of chronic VEGFR-3-specific activation on adipose arbor morphometry using the Adipo-VD mouse, a model of inducible, adipose-specific VEGF-D overexpression. We examined whether adipose tissue innervation was preserved or functionally different in Adipo-VD mice during stress in vivo and if VEGFR-3 signaling afforded neuroprotection to challenged neurons in vitro. Chronic VEGFR-3 signaling in Adipo-VD subcutaneous adipose tissue resulted in a reduction in the dendrite length, dendritic terminal branches (filament length), and dendritic terminal branch volume (filament volume), but increased dendrite branching. We also identified reduced stimulus-evoked excitatory sympathetic nerve activity in Adipo-VD mice. Following 6-hydroxydopamine (6-OHDA) denervation, Adipo-VD dendritic arbors were preserved, including improved dendritic branch volume, length, and dendritic branches than in wildtype tissues. In vitro, we found that chronic elevation of VEGFR-3 signaling in developing mVC neurons changes the dendritic arbor complexity and improves stress-induced structure remodeling. Developing neurons are conferred neuroprotection against stress, potentially by upregulation of proteolytic conversion of pro-BDNF to mature BDNF. Mature neurons, however, display improved dendritic arbor complexity, and unaltered dendritic structural remodeling and improved resistance to stress with VEGFR-3 signaling. Overall, chronically increasing VEGFR-3 signaling in neurons has a synergistic impact on neurosensitization and neuroprotection during stress.

树突状树枝化对于精确神经回路的建立和维护至关重要。据报道，血管内皮生长因子 D (VEGF-D) 被充分表征为“淋巴管生成”生长因子，它通过 VEGF 受体 (VEGFR-3) 信号传导维持成年小鼠海马中的树突状树枝状结构和突触强度。在这里，我们使用 Adipo-VD 小鼠研究了慢性 VEGFR-3 特异性激活对脂肪乔木形态测量的影响，这是一种可诱导的脂肪特异性 VEGF-D 过表达模型。我们检查了在体内应激期间，Adipo-VD 小鼠的脂肪组织神经支配是否保留或功能不同，以及 VEGFR-3 信号传导是否在体外为受挑战的神经元提供神经保护。Adipo-VD 皮下脂肪组织中的慢性 VEGFR-3 信号传导导致树突长度减少，树枝状末端分支（细丝长度）和树枝状末端分支体积（细丝体积），但枝晶分支增加。我们还发现 Adipo-VD 小鼠中刺激诱发的兴奋性交感神经活动减少。在 6-羟基多巴胺 (6-OHDA) 去神经支配后，Adipo-VD 树突状乔木得以保存，包括比野生型组织改善的树突状分支体积、长度和树突状分支。在体外，我们发现发育中的 mVC 神经元中 VEGFR-3 信号的慢性升高会改变树突乔木的复杂性并改善应激诱导的结构重塑。发育中的神经元被赋予对抗压力的神经保护作用，可能是通过上调pro-BDNF 蛋白水解转化为成熟的BDNF。然而，成熟的神经元表现出改进的树突乔木复杂性，和未改变的树突结构重塑和通过 VEGFR-3 信号传导提高对压力的抵抗力。总体而言，神经元中长期增加的 VEGFR-3 信号传导对应激期间的神经敏化和神经保护具有协同影响。