Expression And Effect Of HIF-1?/VEGF In Benign Hyperplasia Of Prostatic Tissue

BackgroundBenign Prostatic Hyperplasia(BPH)is one of the most common chronic progressive diseases in middle-aged and elderly men.Its incidence rate increases with age,and the incidence of men over the age of 80 is as high as 83%.As the disease progresses,patients with BPH often have bladder outlet obstruction(BOO),which causes a series of lower urinary tract symptoms(LUTS).In severe cases,acute urinary retention(AUR)may occur,which seriously affects the quality of life of elderly men.However,BPH patients had histologically proliferative manifestations of prostate epitheliatic um and stromal cells as early as before the onset of symptoms.Factors affecting benign hyperplasia of the prostate tissue involve many aspects such as aging,hormones,metabolism,inflammation,and immunity.However,the specific mechanism is still not clear..Previous studies have shown that hypoxia induced by microcirculation is closely related to the development of BPH.Hypoxia-inducible factor-1(HIF-1)is the core upstream transcription factor of hypoxic environment response.It plays an important role in tissue regeneration,angiogenesis,and cell energy metabolism,and can maintain cells' survival and proliferation under hypoxia.The latest BPH animal model experimental studies have found that the expression of HIF-1?,which is the active subunit of HIF-1,increased in hyperplastic prostate tissue,may participate in the occurrence of prostatic hyperplasia in patients with BPH.VEGF is the major downstream target gene of HIF-1 a,which can promote the formation of new blood vessels,and allow the cells to adapt to the hypoxia.Therefore,We hypothesized that activation of the HIF-1?/VEGF signaling pathway in prostate cells under hypoxia stimulates angiogenesis and proliferation of prostate cells,thereby playing a key role in the hyperplasia changes of prostate tissue in BPH patients.ObjectiveTo study the expression and possible mechanism of HIF-1? and VEGF in hyperplasia prostatic tissue through clinical and animal experiments,and further explore the relationship between the expression level of HIF-1? and the risk of AUR in patients with BPH.Methods1.8 specimens of normal prostate tissue specimens,15 specimens of BPH prostate peripheral tissue,and 116 specimens of BPH hyperplasia prostatic tissue were used in our experiment to detect the expression of HIF-1? and VEGF by immunohisto--chemical staining.Spearman rank correlation Coefficients were used to evaluate the relationship between the expression of VEGF and the expression of HIF-1? in hyperplasia prostatic tissue.2.Chi-square test and logistic regression analysis were used to analyze the relationship between the expression of HIF-1? and the risk of AUR in BPH patients.3.Bilateral internal iliac artery ligation was used to construct SD rat BPH model.The sham-operated group of aged male SD rats was used as control.Prostate tissue was removed from rats by 8 weeks postoperatively.Prostate weight,rat body weight and prostate index were measured in each group to evaluate the prostatic hyperplasia.4.HE staining was used to detect the epithelial-mesenchymal hyperplasia in the prostate tissue of the above two groups.Immunohistochemical staining and Western Blot were used to detect the expression of HIF-la and VEGF in the prostate tissue of the rats.Results1.Immunohistochemical staining showed that there was no positive expression of HIF-1? in normal prostate tissue and BPH prostate peripheral tissue;the positive expression rate of HIF-1? was 74.1%in hyperplasia prostatic tissue from patients with BPH(86/116),of which 42 cases(36.2%)were mildly positive(+)while 44 cases(37.9%)were moderately positive(++),and no strong positive staining.The staining was mainly located in the glandular epithelial cells.Statistical analysis showed that the positive expression rate of HIF-1? in BPH prostatic tissue was significantly higher than that in normal prostate tissue and BPH peripheral tissue(P<0.05).There was no positive expression of VEGF in BPH prostate peripheral tissue.The positive staining rate of VEGF was 64.7%(75/116)in BPH hyperplasia prostate tissue,of which 38(32.8%)were for mild positive(+)and 37(31.9%)for moderately positive(++),and staining was mainly located in the cytoplasm as well as extracellular matrix of glandular epithelial cells.Statistical analysis showed that the expression level of VEGF was positively correlated with the expression level of HIF-1? in hyperplasia prostatic tissue(Spearman correlation coefficient=0.783,P<0.01),suggesting that HIF-1? may play a role in promoting the expression of VEGF in the hyperplasia changes of prostate tissue in BPH patients.2.In 116 patients with BPH,the overall incidence of AUR was 46.6(54/116),and the incidence of AUR in patients with HIF-1?(-),weakly positive,and moderately positive was 20.0%(6/30),38.1%(16/42),72.7%(32/44).Statistical analysis found that the proportion of patients with BPH who had previously had AUR increased with increasing HIF-1? expression.Compared with patients with HIF-1?-negative expression,the risk of AUR in patients with weakly positive HIF-1 a expression was not significantly different(P=0.1>0.05,OR=1.399,95%CI= 0.967-2.023).Patients with moderately positive(++)expression of HIF-la had a significantly increased risk of AUR(P<0.01,OR=2.526,95%CI=1.560-4.091).After adjusting for age,IPSS score,QoL score,and BPH gland weight with logistic regression analysis,the expression level of HIF-1? was still significantly associated with the risk of AUR in BPH patients(P=0.001,OR=0.154,95%CI.= 0.050-0.471),suggesting that the positive expression of HIF-1? is an independent risk factor for AUR in BPH patients.3.At 8 weeks after surgery,it was found that the average weight of the prostate in the hypoxic group was higher than that in the control group(P<0.05).At the same time,there was no significant difference in body weight between the hypoxic group and the control group within 8 weeks(P>0.05),and the prostate index(= prostate weight(mg)/rat body weight(g))was statistically significant(P<0.05).).4.HE staining showed that the proliferation of the epithelial cells in the prostate of rats in the hypoxic group was significantly increased compared with the control group,which made the glandular cavity smaller.Immunohistochemical staining of HIF-1?suggested that the expression of HIF-1? in the prostate of rats with bilateral internal iliac artery ligation was increased,whereas in rats of sham-operated control group,the expression of HIF-la in the prostate was negative.The expression of p65 was positive in both the control group and the surgical ligation group,but it was significantly higher in the surgical group.At the same time,VEGF staining in the sham-operated control group was also negative in the prostate gland,and it was moderately positive in the prostate of BPH rats.The results of western blot were consistent with immunohistochemistry.Conclusion1.HIF-1? and VEGF are highly expressed in hyperplasia prostatic tissue in BPH patients but not in normal prostate tissue and BPH peripheral prostate tissues.2.In the hyperplasia prostatic tissue of BPH,the expression level of VEGF was positively correlated with HIF-la,suggesting that HIF-la may play an important role in the hyperplasia of prostatic tissue in BPH patients by inducing the increase of VEGF protein expression.3.Positive expression of HIF-1? is an independent risk factor for acute urinary retention in patients with BPH.4.Hypoxia can induce prostatic hyperplasia in rats,and the expression of HIF-1? and VEGF in hyperplasia prostatic tissue of rats increases,suggesting that HIF-1 a may play a role in the hyperplasia of prostatic tissue through VEGF.