Abstract
The aim of the present study was to examine whether hypoxia preconditioning could improve therapeutic effects of adipose derived mesenchymal stem cells (AMSCs) for diabetes induced erectile dysfunction (DED). AMSCs were pretreated with normoxia (20% O2, N-AMSCs) or sub-lethal hypoxia (1% O2, H-AMSCs). The hypoxia exposure up-regulated the expression of several angiogenesis and neuroprotection related cytokines in AMSCs, including vascular endothelial growth factor (VEGF) and its receptor FIK-1, angiotensin (Ang-1), basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), stromal derived factor-1 (SDF-1) and its CXC chemokine receptor 4 (CXCR4). DED rats were induced via intraperitoneal injection of streptozotocin (60 mg/kg) and were randomly divided into three groups—Saline group: intracavernous injection with phosphate buffer saline; N-AMSCs group: N-AMSCs injection; H-AMSCs group: H-AMSCs injection. Ten rats without any treatment were used as normal control. Four weeks after injection, the mean arterial pressure (MAP) and intracavernosal pressure (ICP) were measured. The contents of endothelial, smooth muscle, dorsal nerve in cavernoursal tissue were assessed. Compared with N-AMSCs and saline, intracavernosum injection of H-AMSCs significantly raised ICP and ICP/MAP (p<0.05). Immunofluorescent staining analysis demonstrated that improved erectile function by MSCs was significantly associated with increased expression of endothelial markers (CD31 and vWF) (p<0.01) and smooth muscle markers (α-SMA) (p<0.01). Meanwhile, the expression of nNOS was also significantly higher in rats receiving H-AMSCs injection than those receiving N-AMSCs or saline injection. The results suggested that hypoxic preconditioning of MSCs was an effective approach to enhance their therapeutic effect for DED, which may be due to their augmented angiogenesis and neuroprotection.
Highlights
Erectile dysfunction (ED), often referred as impotency in men, is defined as the inability to acquire and/or sustain a sufficient erection function to achieve satisfactory sexual intercourse
adipose derived mesenchymal stem cells (AMSCs) were isolated from ten-week old rats
We found that the phenotype of ADSCs was not significantly influenced by 24 hour’s hypoxia treatment (Fig. 1A)
Summary
Erectile dysfunction (ED), often referred as impotency in men, is defined as the inability to acquire and/or sustain a sufficient erection function to achieve satisfactory sexual intercourse. One of major risks for ED is diabetes mellitus (DM). The causes of ED in diabetic men were complicated and were commonly attributed to functional impairments in blood vessel, muscle, and nerve [5]. DM often induced oxidative stress damage in cavernosum tissues, which may cause the endothelium to loss its physiological properties and shift a vasoconstrictor, prothrombotic and pro-inflammatory state [6,7]. The dysfunction of vascular endothelium is considered to play a major role in the early development of diabetic erectile dysfunction (DED). Smooth muscle dysfunction is observed when DED happens, which may contribute to oxidation of low density lipoprotein (LDL) and increased production of reactive oxygen species (ROS) [8]
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