阴茎血管外周细胞（Pericytes）介导的阴茎血管再生机制的研究及以其开发勃起功能障碍的治疗新靶点

The penis has a specialized vascular bed and erectile dysfunction (ED) is predominantly a disease of vascular origin. Physiologic penile erection requires interaction between vascular endothelial cells (ECs), smooth muscle cells (SMCs) and pericytes in the corpus cavernosum. Functional and structural derangements of these cells play a critical role in the pathophysiology of ED from various causes, such as diabetes and cavernous nerve injury. These observations paved the way to the development of new treatment modalities targeting regeneration of cavernous ECs, SMCs and pericytes. Pericytes were discovered as a population of contractile cells surrounding the ECs of microvessels (arterioles, capillaries, and venules) and were historically defined by their association with capillary ECs. Their presence has been confirmed in a variety of organs and penis tissues. Pericytes are important for vascular maturation by direct contact or communication with ECs, thereby influencing EC proliferation and differentiation as well as the recruitment of SMCs. By contrast, pericyte loss or dropout is a major pathologic feature of diabetic retinopathy, which leads to capillary leakage and macular edema. Moreover, a recent study in an animal model of myocardial infarction showed that intramyocardial transplantation of human pericytes enhances angiogenesis and improves heart function. However,the role of Pericytes in penile erection are as yet largely unknown. Therefore, determination of the role of pericytes in the penis will enhance our understanding of pericyte-mediated penile vascular maturation and the identification of novel therapeutics for ED targeting pericyte function.

阴茎勃起需要海绵体内血管内皮细胞（ECs），平滑肌细胞（SMCs）和血管外周细胞（Pericytes）之间的相互作用。Pericytes被发现为围绕微血管内皮细胞的收缩细胞。Pericytes可通过与EC的直接接触和或沟通，影响EC的增殖和分化及SMCs的补充。相反，Pericytes的缺失或功能降低是糖尿病视网膜病变中毛细血管渗漏和黄斑水肿等主要病因。最近在心肌梗塞动物模型中发现，人类Pericytes的心肌内移植可增强血管生成并改善心脏功能。然而，血管外周细胞在阴茎勃起中的作用目前尚不清楚。本研究组在前期研究中已证明了人类和小鼠阴茎海绵体组织中血管外周细胞的存在，并在糖尿病小鼠ED模型中观察到hepatocyte growth factor通过恢复血管外周细胞从而促进阴茎勃起。因此，进一步阐明阴茎血管外周细胞介导的阴茎血管生成机制，将为寻找ED的新治疗靶点提供巨大帮助。

阴茎海绵体神经损伤(CNI)是一种周围神经损伤性疾病。前列腺癌根治性手术和其他盆腔手术会对阴茎海绵体血管和神经造成器质性损伤，从而明显减弱phosphodiesterase-5抑制剂的作用。.在这里，我们研究了 heme-binding protein 1 (Hebp1) ，已知在双侧CNI小鼠模型和糖尿病小鼠模型中能促进血管生成并改善勃起功能。我们在CNI小鼠模型中发现了一个强有力的神经血管再生因子Hebp1，证明了外源性Hebp1通过提高阴茎海绵体内皮壁细胞和神经元的存活率来改善勃起功能。我们进一步发现，由小鼠海绵体周细胞(MCP)衍生的内源性Hebp1通过细胞外囊泡传递促进CNI小鼠神经血管再生。而且，Hebp1在 CNI小鼠模型中实现这些影响是通过调节claudin信号通路来降低阴茎海绵体血管渗透性达到的。我们的发现为Hebp1作为神经血管再生因子提供了新的见解，证明其在各种周围神经损伤中潜在的治疗应用可能。