Biological aspects in controlling angiogenesis: current progress

Abstract

All living beings continue their life by receiving energy and by excreting waste products. In animals, the arteries are the pathways of these transfers to the cells. Angiogenesis, the formation of the arteries by the development of pre-existed parental blood vessels, is a phenomenon that occurs naturally during puberty due to certain physiological processes such as menstruation, wound healing, or the adaptation of athletes' bodies during exercise. Nonetheless, the same life-giving process also occurs frequently in some patients and, conversely, occurs slowly in some physiological problems, such as cancer and diabetes, so inhibiting angiogenesis has been considered to be one of the important strategies to fight these diseases. Accordingly, in tissue engineering and regenerative medicine, the highly controlled process of angiogenesis is very important in tissue repairing. Excessive angiogenesis can promote tumor progression and lack of enough angiogensis can hinder tissue repair. Thereby, both excessive and deficient angiogenesis can be problematic, this review article introduces and describes the types of factors involved in controlling angiogenesis. Considering all of the existing strategies, we will try to lay out the latest knowledge that deals with stimulating/inhibiting the angiogenesis. At the end of the article, owing to the early-reviewed mechanical aspects that overshadow angiogenesis, the strategies of angiogenesis in tissue engineering will be discussed.

Keywords: Angiogenesis; Anti-angiogenics; Pro-angiogenics; Tissue engineering; Vascularization.

Fig. 1

The processes of angiogenesis, vasculogenesis and arteriogenesis. In the classical form of angiogenesis, the main inducing factor is oxygen depletion, followed by the Hypoxia-inducible Factors (HIFs), which leads to the activation of other factors such as Vascular Endothelial Growth factor (VEGF), Fibroblast Growth Factors (FGF) and Angiopoietin 1 (Ang 1). In this type of angiogenesis, helped by these factors, new vessels grow from existing vessels. Unlike the angiogenesis, in the process of vasculogenesis, new blood vessels are formed by the division of endothelial progenitor cells. In this process, the cells grow through factors such as VEGF, FGF, Ang 1 and Transforming Growth Factor (TGF) (without the need for stimulation by hypoxia). In the arteriogenesis process, most of the lateral connection occurs between the arteries, which requires the division of two types of smooth muscle cells and endothelial cells

Fig. 2

Different steps in physiological angiogenesis. Initially, the endothelial cells of a stable vessel begin to increase permeability. At this stage, the endothelial cells are still firmly held together by the pericytes. Following increased permeability, the plasma protein content, which also contains different pro-angiogenics, would be secreted into the extracellular matrix space. At the same time, due to the activation of proteases, the connection between pericytes and the basement membrane would be weakened and pro-angiogenics-derived from the basement membrane would be secreted into the extracellular matrix space. These factors gradually lead to the onset of endothelial cell proliferation and the formation of new blood vessels

Fig. 3

Effect of different extracellular and intracellular forces on endothelial cells. The relationship that the endothelial cell has with the environment and the extracellular matrix may directly affect gene expression or, by interacting with the cytoskeleton, mediate the change in genome expression and ultimately different cellular responses

Fig. 4

Two main forces that affect angiogenesis. The force exerted by the skeletal muscles is called the mechanical stress force and the force originated by the blood flow is called the shear force

Fig. 5

Angiogenesis in a tumor. Tumor cells by the inflammation they created and by increasing metabolism and subsequently reducing oxygen provide two important signals for angiogenesis. These signals lead to the formation of a vessel by chemotaxis towards the tumor mass (left panel). As it moves away from the blood vessels and closer to the site of cancer (cancer cell accumulation), the oxygen concentration decreases (red triangle), which is one of the strongest stimulants of angiogenesis. Cancer cells also secrete other angiogenic factors, such as VEGF, MMPs, and different ILs by initiating signaling due to a decrease in oxygen pressure, which gradually decreases as they move away from these masses (blue triangle). When the vessels form around the cancerous mass, the vessels are eventually used to allow the cancer cells to migrate to other tissues and trigger metastasis (right panel)

Fig. 6

Overall view on all available anti-angiogenic factors. Between these groups, plant-derived compounds have been wildly studied and there are different classes of them in literature which will be discussed in the corresponded section

Fig. 7

Different proteinous sources of anti-angiogenic peptides