Research Area

Angiogenesis


Introduction of angiogenesis

Angiogenesis is the formation of new blood vessels due to the development of existing capillaries and postcapillary veins. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.

In normal adult coronary arteries, endothelial and vascular smooth muscle cells are nondividing tissue. However, during growth and development and under conditions of ischaemia, hypoxia, inflammation or other stresses, these cells start to migrate and divide. Blood vessel formation passes through several steps, including: the dissolution of the bond between the endothelium and the underlying basement membrane, migration, adhesion and reattachment of the endothelial cells, proliferation and tube formation. Cellular and molecular changes are required for this process, which is complex and as yet poorly understood.

There are for two sources of collateral vessel formation, true angiogenesis or vasculogenesis. Among them, angiogenesis refers to the development of capillaries and the sprouting of small non-muscle vessels from pre-existing capillaries. This process is the main mechanism for increasing collateral blood flow in chronic myocardial ischemia. Vasculogenesis, which refers to the development of blood vessels by de novo, and usually leads to the formation of larger muscle arteries. Although these two processes have different molecular mechanisms, they actually have a similar role in maintaining myocardial perfusion after coronary occlusion. Therefore, angiogenesis is a general term for both ways of producing blood vessels. In the early stage of acute coronary occlusion, the epicardial collateral help to maintain perfusion by enlarging the pre-existing arterioles; as the occlusion time increases, new blood vessels are produced at near the occluded vessels, thereby maintaining blood flow perfusion. In addition, new blood vessels which are produced by true angiogenesis are more likely to maintain subendocardial perfusion, while the blood vessels produced by the pre-existing blood vessels sprout rarely play a role in this process.

Regulation mechanisms of angiogenesis

Angiogenesis is closely linked to the production and release of growth factors. Studies have demonstrated that growth factors play a regulatory role in the formation of new blood vessels. Studies have demonstrated that high levels of b-FGF are detected in pericardial fluid in patients with unstable angina. This process requires not only the presence of growth factors, but also the up-regulation of their respective receptors and the inactivation of the inhibitory effects. Angiogenesis in the heart may be associated with the expression of a variety of substances, including acidic fibroblast growth factor (α-FGF) and b-FGF, VEGF and platelet-derived growth factor (PDGF). Some of these growth factors are constitutively expressed in the myocardium, while others (eg, b-FGF, PDGF) are inducible. Increased expression of b-FGF receptor and VEGF receptors was observed in acute and chronic myocardial ischemia, further suggesting the importance of growth factors during angiogenesis. The superior affinity of heparin (anticoagulant) for b-FGF and many other growth factors has demonstrated the clinical importance of growth factors. For example, b-FGF is stored in an extracellular matrix that binds to heparan sulfate, and heparin protects b-FGF from degradation. In addition, angiogenesis is performed by various angiogenic proteins e.g integrins and prostaglandins.

In addition to the relationship between expression of growth factors (and their receptors) and the development of new blood vessels, there is a close relationship between the release of nitric oxide and the regulation of vascular growth and development. Regulation of angiogenesis by NO is controlled by tyrosine kinase. For example, inhibitors of tyrosine kinase will infect the release of NO by impairing FGF signaling, translocation and DNA synthesis in coronary endothelial cells. Thereby, tyrosine kinase can mediate angiogenic through the function of NO. However, the researchers also discovered that sodium nitroprusside and the NO precursor L-arginine inhibited angiogenesis in the chicken chorioallantoic membrane. In the same study, inhibitors of NO synthase increased these angiogenesis markers. Therefore, the role of NO in different stages of angiogenesis is not obvious and there are differences in diverse species and tissues.

The relationship between cardiovascular disease and angiogenesis

Angiogenesis is an excellent therapeutic target for the treatment of cardiovascular disease. This is a powerful physiological process that is the basis of our body's natural way of reducing the blood supply to vital organs by creating new collateral vessels to overcome ischemic injury. Protein, gene and cell therapies have been used in a large number of preclinical studies to treat cardiac ischemic animal models and peripheral arterial disease models. In these early animal studies, the therapeutic effect was significant and stable, and this new treatment could be rapidly translated into the patient's clinical benefit. Clinical trials have long been based on gene and protein therapies aimed at stimulating angiogenesis in no perfused tissues and organs. However, it has not been successful. Although all of these preclinical studies offer great promise for the transition of angiogenesis treatment from animal to human, the effects of angiogenesis are poor. These failures indicate that our research on angiogenesis systems is not clear enough. These proteins may need to be further presented in a manner that mimics natural signal events, including concentration, spatial and temporal distribution, and their presentation timing with other relevant factors.

References:

  1. Schaper W, Ito WD. Molecular mechanisms of coronary collateral vessel growth. Circulation Res. 1996, 79:911-919.
  2. Ishikawa F, et al. Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor. Nature. 1989, 338:557-562.
  3. Li J, et al. VEGF, flk-1, flt-I expression in a rat model myocardial infarction model of angiogenesis. Am J Physiol. 1996, 270: 1803-1811.
  4. Ziche M, et al. Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J Clin Invest. 1994, 94:2036—44.
  5. Morbidelli L, et al. Nitric oxide mediates mitogenic effect of VEGF on coronary venular endothelium. AmJ Physiol. 1996, 270: 411-415.
  6. Wu HM, et al. Acidic and basic FGF's dilate arterioles of skeletal muscle through a NO-dependent mechanism. Am J Physiol. 1996, 271: 1087-1093.

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