PGE1诱导血管新生的临床和实验研究
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摘要
研究目的
随着人们生活水平的提高,社会老龄化的发展,下肢动脉缺血性疾病明显增多。临床主要表现为肢体疼痛,皮温降低,溃疡形成,严重影响患者的生活质量；而在治疗方面,因为该类疾病大多累及微小动脉和末梢循环,外科手术治疗和血管腔内治疗疗效甚微；内科药物治疗是基础的治疗方法,前列地尔即为该病常用的治疗药物。
前列地尔(PGE1)具有扩张外周血管,抑制血小板聚集,改善内皮细胞功能的作用,可以有效地增加局部血流量,改善微循环,增加局部组织的供氧量,能够一定程度地改善串肢症状,减轻疼痛,甚至促进溃疡愈合等,在临床上得到广泛应用。
在临床应用PGE1治疗下肢动脉供血不足的患者中,我们发现部分患者在治疗一段时间以后,不仅临床症状得到一定的改善,而且在停药一段时间药物作用消失后,疼痛、皮温升高等症状并没有出现加重,因此我们考虑是否PGE1有促进血管新生的作用?是新生血管改善了患者局部组织的血液供应,从而达到了较好的、持久的治疗效果?如果是新生血管在起作用,那么促进血管新生的机制又是什么呢?本研究通过临床和试验研究两个方面来揭示PGE1的血管新生作用和促进血管新生的作用机制。
研究方法
临床部分本组患者15例,男9例,女6例；下肢动脉广泛闭塞,以膝下动脉闭塞为主,末梢循环闭塞严重；临床表现为下肢疼痛,10例患者出现静息痛,跛行距离为20-150米,局部溃疡形成者6例；所有患者给予10ug PGE1,经静脉注射,一日二次,两周为一疗程。治疗过程中观察并记录患者疼痛、皮温变化、溃疡愈合等情况；比较治疗前后跛行距离、经皮氧分压(TCPO2)情况,行彩超、CTA/MRA以了解缺血部位血供情况。
实验部分实验采用人脐静脉内皮细胞(HUVECs), HUVECs复苏、培养、传代,取3-6代传代细胞,加入细胞培养液,配置成1×105/ml的细胞混悬液,加入PGE1后继续培养,测定不同时间、不同剂量下血管内皮生长因子(VEGF)含量、HUVECs增殖、转移情况,并与对照组比较；同时设置血管新生阻滞剂(贝伐单抗)组,以了解贝伐单抗对血管内皮生长因子(VEGF)含量、HUVECs增殖、迁移的影响；ERK和P38磷酸化信号通路广泛参与细胞有丝分裂,在促进内皮细胞增殖、转移及管道形成方面发挥着重要的作用,我们猜想PGE1在促进血管新生时亦有可能是通过ERK和P38磷酸化信号通路来实现的,测定HUVECs、PGE1+HUVECs、P098059(ERK磷酸化阻滞剂)+HUVECs、P203580 (P38磷酸化阻滞剂)+HUVECs培养液中细胞增殖、迁移和管道形成情况。
实验结果
临床部分
PGE1治疗二周后,静息痛明显减轻,10例治疗前夜间不能入睡的患者8例可以安静入睡；跛行距离有所增加,80-270米,平均增加80米；6例局部溃疡形成者溃疡面积明显缩小,2例患者溃疡愈合；治疗后和治疗后二周TCP02较治疗前明显增加,治疗后和治疗二周后TCP02无明显变化；治疗后二周彩超示缺血组织(腓肠肌)内血流信号较用药前明显增加,CTA示缺血部位毛细血管数量增多。
实验部分
PGE1促进HUVECs分泌VEGF,促进HUVECs增殖、迁移。
血管新生阻滞剂--贝伐单抗能够阻断PGE1诱导的VEGF含量的增加和HUVECs的增殖和迁移。
PGE1通过ERK和P38磷酸化途径促进内皮细胞的增殖和迁移。
ERK和P38磷酸化阻滞剂——P098059和P203580能够阻断PGE1诱导的ERK和P38磷酸化,使HUVECs的增殖、迁移和管道形成明显减少。
实验结论
PGE1能够促进缺血部位血管新生。
PGE1能够诱导HUVECs分泌VEGF;并通过VEGF促进内皮细胞增殖、迁移和类管道形成。
PGE1诱导HUVECs分泌VEGF途径是通过ERK和P38磷酸化实现的。
Background&Obj ective
As the rising of living standard and the aging of the social development, the lower limb artery ischemic diseases are increasing obviously. The mainly clinical feature includes physical pain, skin temperature lower and ulcer formation. For the disease mostly involving the tiny artery and peripheral circulation, both surgical and intracavitary treatment are little effect. The medications are the foundational methods, PGE1 is the commonly used medicine.
PGE1 can expand peripheral vascular, inhibit platelet aggregation and improve the function of endothelial cells, can increase local blood flow, improve microcirculation and increase the oxygen for local organization.
In the clinical application, we found that some patients who used PGE1, found the symptoms have been improved, and in the period of stopping the drugs, clinical features, such as the paining and skin temperature rising higher, did not appear aggravating, so we consider whether PGE1 acts the role of angiogenesis? Are the new blood vessels improving the blood supply of the local tissue? If it is, what's the mechanism of angiogenesis? The clinical and experimental researches are going to reveal the angiogenesis and the mechanism.
Methods
Clinical section
This group of patients with 15 cases, male 9 cases, female 6; The low limb artery occlusion is wide, and peripheral circulation block is serious; 10 patients appeared resting pain, the limp distances were 20-150 m,6 cases have the local ulceration. All of the patients were given PGE110 ug by intravenous injection, two times per day, and two weeks for one period of treatment. Observed and recorded the pain, skin temperature change and ulcer healing, limp distance and percutaneous oxygen partial pressure (TcpO2), with color dopplar ultrasound, CTA/MRA to test the blood supply to the ischemia site.
Experiment section
The experiment used the human umbilical vein endothelial cells(HUVECs), HUVECs were recovered, culturing and subculturing, took 3-6 generations passage cell, added cell supernatant, configured to 1 x105/ml of cell suspension liquid; added PGE1 and continue to cultivate. Determined contention of vascular endothelial growth factor (VEGF), HUVECs proliferation, transfer, and compared with control groups; And setting angiogenesis blockers (Beacizumab) group, to observe the influence of Bevacizumab for VEGF), HUVECs proliferation, the migration and pipe formed; P38.and ERK phosphorylation signaling pathways widely participate in mitosis, and playing an important role in promoting endothelial cell proliferation, transfer and pipe formed, we guess PGE1 also may be through the ERK and P38 phosphorylation to in promote angiogenesis. So put PGE1, P098059 (ERK phosphorylation blockers), P203580 (P38 phosphorylation blockers) into HUVECs to see the growing of the cell such as proliferation, migration and pipe formed.
Result
Clinical section
PGE1 had been used two weeks, resting pain were reduced significantly,8 cases who couldn't sleep in night before treatment can be quiet sleep. The limp distance was increased, the number were from 80 to 270 meters, an average of 80m; 6 cases of the local ulcer area were decreased, two patients'ulcer were healing; TcpO2 were significantly increased. Compared with 2 weeks and 4 weeks, the paining, the limp distance and TcpO2were no changed; Compared with the beginning, the ultrasound indicated that the flow signals of ischemic tissues were colourful in 2 weeks and 4 weeks. And the capillary vessels were richer according to CTA images.
Experimental section
PGE1 induce HUVECs to secrete VEGF, and induce HUVECs Proliferation, migration and pipe formed.
Angiogenesis blockers-bevacizumab could block the pathway of PGE1 induction of VEGF and decreased the proliferation, migration and pipe formed of HUVECs.
PGE1 promoted HUVECs proliferation and migration and pipe formed by the pathway with ERK and P38 phosphorylation, ERK and P38 phosphorylation blockers-P098059 and P203580 can block ERK and P38 phosphorylation, make HUVECs proliferation, migration and pipe formed less significantly.
Conclusions:
PGE1 can promote ischemia parts angiogenesis.
PGE1 can induce HUVECs to secret VEGF and promote HUVECs proliferation and migration and pipe formed.
The mechanism of angiogenesis is by the pathway of ERK and P38 phosphorylation.
随着人们生活水平的提高,社会老龄化的发展,下肢动脉缺血性疾病明显增多。临床主要表现为肢体疼痛,皮温降低,溃疡形成,严重影响患者的生活质量；而在治疗方面,因为该类疾病大多累及微小动脉和末梢循环,外科手术治疗和血管腔内治疗疗效甚微；内科药物治疗是基础的治疗方法,前列地尔即为该病常用的治疗药物。
前列地尔(PGE1)具有扩张外周血管,抑制血小板聚集,改善内皮细胞功能的作用,可以有效地增加局部血流量,改善微循环,增加局部组织的供氧量,能够一定程度地改善串肢症状,减轻疼痛,甚至促进溃疡愈合等,在临床上得到广泛应用。
在临床应用PGE1治疗下肢动脉供血不足的患者中,我们发现部分患者在治疗一段时间以后,不仅临床症状得到一定的改善,而且在停药一段时间药物作用消失后,疼痛、皮温升高等症状并没有出现加重,因此我们考虑是否PGE1有促进血管新生的作用?是新生血管改善了患者局部组织的血液供应,从而达到了较好的、持久的治疗效果?如果是新生血管在起作用,那么促进血管新生的机制又是什么呢?本研究通过临床和试验研究两个方面来揭示PGE1的血管新生作用和促进血管新生的作用机制。
研究方法
临床部分本组患者15例,男9例,女6例；下肢动脉广泛闭塞,以膝下动脉闭塞为主,末梢循环闭塞严重；临床表现为下肢疼痛,10例患者出现静息痛,跛行距离为20-150米,局部溃疡形成者6例；所有患者给予10ug PGE1,经静脉注射,一日二次,两周为一疗程。治疗过程中观察并记录患者疼痛、皮温变化、溃疡愈合等情况；比较治疗前后跛行距离、经皮氧分压(TCPO2)情况,行彩超、CTA/MRA以了解缺血部位血供情况。
实验部分实验采用人脐静脉内皮细胞(HUVECs), HUVECs复苏、培养、传代,取3-6代传代细胞,加入细胞培养液,配置成1×105/ml的细胞混悬液,加入PGE1后继续培养,测定不同时间、不同剂量下血管内皮生长因子(VEGF)含量、HUVECs增殖、转移情况,并与对照组比较；同时设置血管新生阻滞剂(贝伐单抗)组,以了解贝伐单抗对血管内皮生长因子(VEGF)含量、HUVECs增殖、迁移的影响；ERK和P38磷酸化信号通路广泛参与细胞有丝分裂,在促进内皮细胞增殖、转移及管道形成方面发挥着重要的作用,我们猜想PGE1在促进血管新生时亦有可能是通过ERK和P38磷酸化信号通路来实现的,测定HUVECs、PGE1+HUVECs、P098059(ERK磷酸化阻滞剂)+HUVECs、P203580 (P38磷酸化阻滞剂)+HUVECs培养液中细胞增殖、迁移和管道形成情况。
实验结果
临床部分
PGE1治疗二周后,静息痛明显减轻,10例治疗前夜间不能入睡的患者8例可以安静入睡；跛行距离有所增加,80-270米,平均增加80米；6例局部溃疡形成者溃疡面积明显缩小,2例患者溃疡愈合；治疗后和治疗后二周TCP02较治疗前明显增加,治疗后和治疗二周后TCP02无明显变化；治疗后二周彩超示缺血组织(腓肠肌)内血流信号较用药前明显增加,CTA示缺血部位毛细血管数量增多。
实验部分
PGE1促进HUVECs分泌VEGF,促进HUVECs增殖、迁移。
血管新生阻滞剂--贝伐单抗能够阻断PGE1诱导的VEGF含量的增加和HUVECs的增殖和迁移。
PGE1通过ERK和P38磷酸化途径促进内皮细胞的增殖和迁移。
ERK和P38磷酸化阻滞剂——P098059和P203580能够阻断PGE1诱导的ERK和P38磷酸化,使HUVECs的增殖、迁移和管道形成明显减少。
实验结论
PGE1能够促进缺血部位血管新生。
PGE1能够诱导HUVECs分泌VEGF;并通过VEGF促进内皮细胞增殖、迁移和类管道形成。
PGE1诱导HUVECs分泌VEGF途径是通过ERK和P38磷酸化实现的。
Background&Obj ective
As the rising of living standard and the aging of the social development, the lower limb artery ischemic diseases are increasing obviously. The mainly clinical feature includes physical pain, skin temperature lower and ulcer formation. For the disease mostly involving the tiny artery and peripheral circulation, both surgical and intracavitary treatment are little effect. The medications are the foundational methods, PGE1 is the commonly used medicine.
PGE1 can expand peripheral vascular, inhibit platelet aggregation and improve the function of endothelial cells, can increase local blood flow, improve microcirculation and increase the oxygen for local organization.
In the clinical application, we found that some patients who used PGE1, found the symptoms have been improved, and in the period of stopping the drugs, clinical features, such as the paining and skin temperature rising higher, did not appear aggravating, so we consider whether PGE1 acts the role of angiogenesis? Are the new blood vessels improving the blood supply of the local tissue? If it is, what's the mechanism of angiogenesis? The clinical and experimental researches are going to reveal the angiogenesis and the mechanism.
Methods
Clinical section
This group of patients with 15 cases, male 9 cases, female 6; The low limb artery occlusion is wide, and peripheral circulation block is serious; 10 patients appeared resting pain, the limp distances were 20-150 m,6 cases have the local ulceration. All of the patients were given PGE110 ug by intravenous injection, two times per day, and two weeks for one period of treatment. Observed and recorded the pain, skin temperature change and ulcer healing, limp distance and percutaneous oxygen partial pressure (TcpO2), with color dopplar ultrasound, CTA/MRA to test the blood supply to the ischemia site.
Experiment section
The experiment used the human umbilical vein endothelial cells(HUVECs), HUVECs were recovered, culturing and subculturing, took 3-6 generations passage cell, added cell supernatant, configured to 1 x105/ml of cell suspension liquid; added PGE1 and continue to cultivate. Determined contention of vascular endothelial growth factor (VEGF), HUVECs proliferation, transfer, and compared with control groups; And setting angiogenesis blockers (Beacizumab) group, to observe the influence of Bevacizumab for VEGF), HUVECs proliferation, the migration and pipe formed; P38.and ERK phosphorylation signaling pathways widely participate in mitosis, and playing an important role in promoting endothelial cell proliferation, transfer and pipe formed, we guess PGE1 also may be through the ERK and P38 phosphorylation to in promote angiogenesis. So put PGE1, P098059 (ERK phosphorylation blockers), P203580 (P38 phosphorylation blockers) into HUVECs to see the growing of the cell such as proliferation, migration and pipe formed.
Result
Clinical section
PGE1 had been used two weeks, resting pain were reduced significantly,8 cases who couldn't sleep in night before treatment can be quiet sleep. The limp distance was increased, the number were from 80 to 270 meters, an average of 80m; 6 cases of the local ulcer area were decreased, two patients'ulcer were healing; TcpO2 were significantly increased. Compared with 2 weeks and 4 weeks, the paining, the limp distance and TcpO2were no changed; Compared with the beginning, the ultrasound indicated that the flow signals of ischemic tissues were colourful in 2 weeks and 4 weeks. And the capillary vessels were richer according to CTA images.
Experimental section
PGE1 induce HUVECs to secrete VEGF, and induce HUVECs Proliferation, migration and pipe formed.
Angiogenesis blockers-bevacizumab could block the pathway of PGE1 induction of VEGF and decreased the proliferation, migration and pipe formed of HUVECs.
PGE1 promoted HUVECs proliferation and migration and pipe formed by the pathway with ERK and P38 phosphorylation, ERK and P38 phosphorylation blockers-P098059 and P203580 can block ERK and P38 phosphorylation, make HUVECs proliferation, migration and pipe formed less significantly.
Conclusions:
PGE1 can promote ischemia parts angiogenesis.
PGE1 can induce HUVECs to secret VEGF and promote HUVECs proliferation and migration and pipe formed.
The mechanism of angiogenesis is by the pathway of ERK and P38 phosphorylation.
引文
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