The coordination between neurogenesis and angiogenesis plays an important role in nerve tissue development and regeneration. Recently, using bioactive materials to drive neurogenic and angiogenic responses has gained increasing attention. Understanding the neurovascular link between regulatory cues offers valuable insight into the mechanisms underlying nerve regeneration and the design of new bioactive materials. In this study, we utilized a dual-functionalized peptide nanofiber hydrogel presenting the brain-derived neurotrophic factor and vascular endothelial growth factor mimetic peptides RGIDKRHWNSQ (RGI) and KLTWQELYQLKYKGI (KLT) to construct an artificial neurovascular microenvironment. The dual-functionalized peptide nanofiber hydrogel enhanced the neurite outgrowth of pheochromocytoma (PC12) cells and tube-like structures formation of human umbilical vein endothelial cells (HUVECs) in vitro, and promoted rapid lesion infiltration of neural and vascular cells in a rat brain injury model. Using indirect co-culture models, we found that the dual-functionalized peptide hydrogel effectively mediated neurovascular crosstalk by regulating secretion of paracrine factors from PC12 cells and HUVECs. When the two cells types were directly co-cultured on the dual-functionalized peptide hydrogel, the efficiency of cell-cell communication was enhanced, which further accelerated the differentiation and maturation of PC12 cells with an increased number of pseudopodia and spread morphology, and HUVECs tube-like structure formation. In summary, the dual-functionalized peptide nanofiber hydrogel successfully formed an artificial neurovascular niche to directly regulate the behaviors of neural and vascular cells and promote their neurovascular crosstalk through paracrine signaling and direct cell-cell contact.

神经发生和血管发生之间的协调在神经组织发育和再生中起重要作用。最近，使用生物活性材料来驱动神经源性和血管生成性反应越来越受到关注。了解调节线索之间的神经血管联系为了解神经再生的机制和新生物活性材料的设计提供了宝贵的见解。在这项研究中，我们利用具有脑源性神经营养因子和血管内皮生长因子模拟肽 RGIDKRHWNSQ (RGI) 和 KLTWQELYQLKYKGI (KLT) 的双功能肽纳米纤维水凝胶构建人工神经血管微环境。体外，并促进大鼠脑损伤模型中神经和血管细胞的快速病变浸润。使用间接共培养模型，我们发现双功能肽水凝胶通过调节 PC12 细胞和 HUVEC 的旁分泌因子的分泌，有效地介导了神经血管串扰。当两种细胞类型在双功能肽水凝胶上直接共培养时，细胞间通讯效率得到提高，从而进一步加速了 PC12 细胞的分化和成熟，伪足和扩散形态的数量增加，HUVECs管状结构形成。总之，