背景:海绵状神经(CN)损伤,由前列腺切除术和糖尿病引起的,在患者和动物模型的阴茎海绵体中启动重塑过程(平滑肌细胞凋亡和胶原蛋白增加),这是勃起功能障碍(ED)的根本原因,Sonichedgehog(SHH)通路在阴茎对神经支配的反应中起着至关重要的作用,胶原蛋白随着SHH抑制而增加,随着SHH处理而减少。
目的:我们检查了SHH如何防止阴茎重塑和CN损伤引起的胶原蛋白增加的部分机制是否涉及骨形态发生蛋白4(BMP4)和gremlin1(GREM1),并检查了SHH之间的关系。ED患者和CN损伤大鼠模型阴茎中的BMP4、GREM1和胶原,SHH抑制,SHH,BMP4和GREM1治疗。
方法:佩罗尼病的海绵体(对照),前列腺切除术,获得糖尿病性ED患者(N=30)。成年SpragueDawley大鼠(n=90)接受(1)CN挤压(1-7天)或假手术;(2)CN损伤和BMP4,GREM1或小鼠血清白蛋白(对照)通过Affi-Gel珠或肽两亲物(PA)治疗14天;(3)5E1SHH抑制剂,IgG,或磷酸盐缓冲盐水(对照)处理2至4天;或(4)用小鼠血清白蛋白或SHH压碎CN9天。
结果:进行了BMP4和GREM1的免疫组织化学和Western分析,以及通过羟脯氨酸和三色染色进行的胶原蛋白分析。
结果:在前列腺切除术的海绵体平滑肌中发现了BMP4和GREM1蛋白,糖尿病,和佩罗尼的病人,在大鼠平滑肌中,交感神经纤维,神经束,血管,还有尿道.在CN损伤和BMP4治疗的大鼠中,胶原蛋白减少了25.4%(P=.02),在CN损伤和GREM1治疗的大鼠中,胶原蛋白增加了61.3%(P=.005)。三色染色显示用GREM1处理的大鼠中胶原蛋白增加。西方分析发现,前列腺切除术和糖尿病患者的海绵体中BMP4和GREM1增加,和CN损伤后(1-2天)在我们的大鼠模型。BMP4和GREM1的定位随SHH抑制而改变。SHH处理增加了BMP4和GREM1的单体形式,改变了它们的信号传导范围。
结论:更好地了解阴茎重塑以及神经支配丧失是如何发生纤维化的,对于开发新的ED疗法至关重要。
■SHH,BMP4,GREM1和胶原蛋白在阴茎中是复杂的。
结论:BMP4和GREM1是影响胶原蛋白的SHH下游靶标,可能与SHH合作预防阴茎重塑和ED。
BACKGROUND: Cavernous nerve (CN) injury, caused by prostatectomy and diabetes, initiates a remodeling process (smooth muscle apoptosis and increased collagen) in the corpora cavernosa of the penis of patients and animal models that is an underlying cause of erectile dysfunction (ED), and the Sonic hedgehog (SHH) pathway plays an essential role in the response of the penis to denervation, as collagen increases with SHH inhibition and decreases with SHH treatment.
OBJECTIVE: We examined if part of the mechanism of how SHH prevents penile remodeling and increased collagen with CN injury involves bone morphogenetic protein 4 (BMP4) and gremlin1 (GREM1) and examined the relationship between SHH, BMP4, GREM1, and collagen in penis of ED patients and rat models of CN injury, SHH inhibition, and SHH, BMP4, and GREM1 treatment.
METHODS: Corpora cavernosa of Peyronie\'s disease (control), prostatectomy, and diabetic ED patients were obtained (N = 30). Adult Sprague Dawley rats (n = 90) underwent (1) CN crush (1-7 days) or sham surgery; (2) CN injury and BMP4, GREM1, or mouse serum albumin (control) treatment via Affi-Gel beads or peptide amphiphile (PA) for 14 days; (3) 5E1 SHH inhibitor, IgG, or phosphate-buffered saline (control) treatment for 2 to 4 days; or (4) CN crush with mouse serum albumin or SHH for 9 days.
RESULTS: Immunohistochemical and Western analysis for BMP4 and GREM1, and collagen analysis by hydroxyproline and trichrome stain were performed.
RESULTS: BMP4 and GREM1 proteins were identified in corpora cavernosa smooth muscle of prostatectomy, diabetic, and Peyronie\'s patients, and in rat smooth muscle, sympathetic nerve fibers, perineurium, blood vessels, and urethra. Collagen decreased 25.4% in rats with CN injury and BMP4 treatment (P = .02) and increased 61.3% with CN injury and GREM1 treatment (P = .005). Trichrome stain showed increased collagen in rats treated with GREM1. Western analysis identified increased BMP4 and GREM1 in corpora cavernosa of prostatectomy and diabetic patients, and after CN injury (1-2 days) in our rat model. Localization of BMP4 and GREM1 changed with SHH inhibition. SHH treatment increased the monomer form of BMP4 and GREM1, altering their range of signaling.
CONCLUSIONS: A better understanding of penile remodeling and how fibrosis occurs with loss of innervation is essential for development of novel ED therapies.
UNASSIGNED: The relationship between SHH, BMP4, GREM1, and collagen is complex in the penis.
CONCLUSIONS: BMP4 and GREM1 are downstream targets of SHH that impact collagen and may be useful in collaboration with SHH to prevent penile remodeling and ED.