生长因子的协同作用与新血管形成的研究进展

缺血性疾病的血管重建不只依赖于血管新生,还需骨髓来源的前体细胞的参与.缺血本身不仅能动员血管前体细胞,而且能够增强它们向内皮细胞分化的能力.有许多生长因子如血管内皮生长因子、血小板源性生长因子等能募集骨髓来源的内皮前体细胞到血管重建部位.但是,缺血诱导的血管形成往往不能完全弥补外周血管病变和动脉闭塞所引起的血流减少,并且单一的生长因子作用也不能诱导成熟稳定的血管形成,同时易出现并发症而制约了其临床应用.因此如何利用生长因子动员血管前体细胞参与血管新生,并通过其协同作用形成稳定的功能性的血管成为研究的热点.本文就生长因子协同作用参与新血管形成方面作一综述.     

Contribution of arteriogenesis and angiogenesis to postocclusive hindlimb perfusion in mice

The goal of this study was to examine the mechanisms of vascular growth that lead to the restoration of perfusion in a peripheral vascular disease model in mice. We monitored blood flow recovery and measured vascular growth in inbred strains of mice following femoral artery occlusion. Acute collateral blood flow to the hindlimb was lowest in Balb/C mice, causing intense ischemia, and showed a slower recovery (more than 21 days to 50% normal) than C57Bl/6 which had a 7-fold higher acute collateral flow and a fast recovery (3 days). Collateral vessels were enlarged by proliferation of ECs and SMCs. Capillary density increased in the lower limbs of Balb/Cs (1.7-fold) and of sv129s. Tissue oxygen saturation recovered faster than flow in all strains. Morphometry of mature collaterals showed a diameter increase of 2.1-2.4 fold. The increase in total vessel wall area exceeded that of the femoral artery by 1.4-fold and the common lumenal area by 1.6-fold. Infusion of the growth factor peptide FGF-2 by osmotic minipump accelerated arteriogenesis but inhibited the angiogenic response probably because it prevented ischemia. Conclusion: the speed of arteriogenesis is inversely related to the intensity of ischemia, and arteriogenesis is by far the most efficient mechanism to increase blood flow after femoral artery occlusion. De novo arteriogenesis was not observed.     

侧枝循环形成机制研究进展

侧枝循环形成是缺血继发的一种代偿机制。脑缺血后内源性促血管生长因子表达增加,启动血管新生和动脉生成,加速缺血区侧枝循环形成,改善缺血区域血液供应。     

New therapeutic option for autosomal dominant polycystic kidney disease patients with enlarged kidney and liver

The kidneys of patients with autosomal dominant polycystic kidney disease (ADPKD) usually continue to increase in size even after patients begin dialysis, and mass effects can lead to severe complications. Thus far, renal manifestations of this disorder have been discussed only from the viewpoint of cyst formation or cytogenesis, not from that of vascular abnormality. Because kidneys in ADPKD patients are usually supplied by well-developed arteries, we attempted renal contraction therapy in ADPKD patients with renal transcatheter arterial embolization (TAE) using intravascular coils. Mainly peripheral branches of renal arteries encircling the cysts were embolized. Our treatment has been confirmed to be effective in 266 patients until 2005. Renal size continued to decrease to 53% of the pre-TAE after 1 year. Almost all patients have had improved quality of life and nutritional status. We next tried TAE in 76 intractable patients with symptomatic polycystic liver. We tried to embolize only the hepatic segments replaced by cystic lesions in which the hepatic arteries were well-developed but the intrahepatic portal vein was obstructed. Sixty-four patients have had a good clinical course with this method. Based on our observation of ADPKD through treatment with TAE, we speculate that cyst growth in both the kidney and the liver progresses via the mechanism of 'arteriogenesis' of large vessels as well as 'angiogenesis' of small vessels.     

Ultrastructure and molecular histology of rabbit hind-limb collateral artery growth (arteriogenesis)

Previous studies in the canine heart had shown that the growth of collateral arteries occurs via proliferative enlargement of pre-existing arteriolar connections (arteriogenesis). In the present study, we investigated the ultrastructure and molecular histology of growing and remodeling collateral arteries that develop after femoral artery occlusion in rabbits as a function of time from 2 h to 240 days after occlusion. Pre-existent arteriolar collaterals had a diameter of about 50 μm. They consisted of one to two layers of smooth muscle cells (SMCs) and were morphologically indistinguishable from normal arterioles. The stages of arteriogenesis consisted of arteriolar thinning, followed by transformation of SMCs from the contractile- into the proliferative- and synthetic phenotype. Endothelial cells (ECs) and SMCs proliferated, and SMCs migrated and formed a neo-intima. Intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) showed early upregulation in ECs, which was accompanied by accumulation of blood-derived macrophages. Mitosis of ECs and SMCs started about 24 h after occlusion, whereas adhesion molecule expression and monocyte adhesion occurred as early as 12 h after occlusion, suggesting a role of monocytes in vascular cell proliferation. Treatment of rabbits with the pro-inflammatory cytokine MCP-1 increased monocyte adhesion and accelerated vascular remodeling. In vitro shear-stress experiments in cultured ECs revealed an increased phosphorylation of the focal contacts after 30 min and induction of ICAM-1 and VCAM-1 expression between 2 h and 6 h after shear onset, suggesting that shear stress may be the initiating event. We conclude that the process of arteriogenesis, which leads to the positive remodeling of an arteriole into an artery up to 12 times its original size, can be modified by modulators of inflammation. Received: 16 March 1999 / Accepted: 4 August 1999     

Isolation and transduction of monocytes: promising vehicles for therapeutic arteriogenesis

Background and aims Augmentation of collateral vessel growth (arteriogenesis) is of particular clinical interest for the treatment of vascular occlusive disease. Monocytes play a key role for arteriogenesis. They localize to areas of collateral development and create a highly arteriogenic environment. “Homing” of ex vivo genetically engineered monocytes could therapeutically be exploited for augmentation of arteriogenesis. However, isolation and ex vivo transduction of monocytes is problematic. Methods In this study, we established a valid method of monocyte isolation from peripheral blood and evaluated different in vitro transduction methods. Results Our results revealed that liposomes and electroporation were unsuccessful for monocyte transduction. However, high-efficiency gene transfer (almost 95%) was achieved by adenoviral infection. Subsequent homing of virally transduced monocytes to sites of arteriogenesis could be demonstrated. Conclusion Our study may offer a new method for the augmentation of arteriogenesis, all of which makes the ultimate goal of applying this strategy to humans for therapy of vascular disease eminently attractive. Best of Forum Papers presented at the Annual Meeting of the German Society of Surgery, 2–5 May 2006, Berlin, Germany     

Advances in neovascularization after diabetic ischemia

With the high incidence of diabetes around the world, ischemic complications cause a serious influence on people’s production and living. Neovascularization plays a significant role in its development. Therefore, neovascularization after diabetic ischemia has aroused attention and has become a hot spot in recent years. Neovascularization is divided into angiogenesis represented by atherosclerosis and arteriogenesis characterized by coronary collateral circulation. When mononuclear macrophages successively migrate to the ischemia anoxic zone after ischemia or hypoxia, they induce the secretion of cytokines, such as vascular endothelial growth factor and hypoxia-inducible factor, activate signaling pathways such as classic Wnt and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathways, trigger oxidative stress response, activate endothelial progenitor cells or enter the glycolysis or lactic acid process and promote the formation of new blood vessels, remodeling them into mature blood vessels and restoring blood supply. However, the hypoglycemic condition has different impacts on neovascularization. Consequently, this review aimed to introduce the mechanisms of neovascularization after diabetic ischemia, increase our un-derstanding of diabetic ischemic complications and their therapies and provide more treatment options for clinical practice and effectively relieve patients’ pain. It is believed that in the near future, neovascularization will bring more benefits and hope to patients with diabetes.     

Cellular and Pharmacological Targets to Induce Coronary Arteriogenesis

The formation of collateral vessels (arteriogenesis) to sustain perfusion in ischemic tissue is native to the body and can compensate for coronary stenosis. However, arteriogenesis is a complex process and is dependent on many different factors. Although animal studies on collateral formation and stimulation show promising data, clinical trials have failed to replicate these results. Further research to the exact mechanisms is needed in order to develop a pharmalogical stimulant. This review gives an overview of recent data in the field of arteriogenesis.