In the process of wound healing, angiogenesis is also known as neovascularization. The process commences in lined with the proliferation of the fibroblast when the endothelial cells mover towards the wound site. Oxygen and other nutrients are required for the formation of epithelial cells and the activity of fibroblasts. In comparison to the fibroblast and epidermal mitigation, angiogenesis is crucial for other stages of wound healing. The process of angiogenesis is complex and occurs in the following stages:
Latent period: In this stage, vasodilation and premeabilisation are known to permit leukocyte extravasation during the haemostatic and inflammatory phase. Decontamination and phagocytic debridement is also observed in the wound area. The expansion of the existing collagenous and extracellular matrix is known to occur before tissue swelling.
Endothelial activation: The next step constitutes of healing, wherein the macrophages commence to secrete growth and endothelial chemotactic factors close to endothelial cells. They respond by reducing and retracting cell junctions and remove themselves from the endothelium. These endothelial cells display a large nucleoli (Bao, P., t al. 2008)
Degradation of endothelial basement membrane: Any existing vascular basal lamina cells are broken down by the mast, macrophages, and endothelial cells with help of proteases.
Vascular sprouting: In this stage, the detached endothelial cells would divide and move towards the wound chemotactically due to the breakdown of the endothelial basement membrane. Ambient hypoxia and acidosis lead to vascular sprouting. hypoxia inducible factor (HIF) is closely associated with the genes such as VEGF and GLUT1.
Vascular maturation: This stage is characterized by the development of new endothelial extracellular matrix which is proceeded by the formation of the basal lamina (Demidova-Rice, T. N., Durham, J. T., & Herman, I. M. 2012).
AMPK (Adenosine monophosphate-activated protein kinase) in ROS (reactive oxygen species) and angiogenesis: Adenosine monophosphate-activated protein kinase constitutes of 3 proteins that form a functional enzyme which is known to be found as yeast in humans. It is mainly expressed and present in the brain, liver, and muscle (skeletal). The stimulation of the hepatic fatty acid, inhibition of cholesterol synthesis, ketogenesis, triglyceride synthesis, and lipogenesis are net effect of the AMPK activation (Pung, Y. F., et al. 2013)
The AMP-activated protein kinase (AMPK) is known as for the phosphorylation of the 3-hydroxy 3-methylglutaryl coenzyme A reductase. This enzyme is known to be involved in the biosynthesis of cholesterol. Increased intracellular concentrations of AMP is known to be activate the AMPK. It is also known as the metabolite-sensing kinase. Cellular energy is mainly conserved and initiated by the AMPK. The activity of the AMPK can be controlled in the muscle cells along with metabolic control by regulating a few stimuli. These stimuli are known to be linked with the cellular ATP levels. These levels are known to be associated with hypoxia and fluid shear stress. Some of the other factors linked with the cellular ATP levels include hormones (adiponectin) and Ca2+-elevating agonists. The AMPK is known to play a crucial role in angiogenesis and inflammation by the regulation of nitric oxide, small G protein, and fatty acid production. The activation of AMPK based on current evidence is known to prevent vascular complications in humans that are linked with metabolic syndrome (Zou, M.-H., & Wu, Y. 2008)
Many intracellular systems are known to be regulated by the activation of the AMPK such as the β-oxidation of fatty acids, cellular uptake of glucose, biogenesis of glucose transporter 4 (GLUT4), and other functions of the mitochondria. The AMPK’s ability to recognise and react to varying fluctuations of the AMP:ATP ratio due to its energy-sensing capability is mainly observed in oxidative stress species, exercise, and training (Zou, M.-H., & Wu, Y. 2008 and Pung, Y. F., et al. 2013)
Vitamin D in angiogenesis
Based on current evidence, the process of angiogenesis is complex and involves the formation of new blood vesicles from existing vesciles. The most important feature of angiogenesis includes its importance and potential in local and primary tumour invasion along with metastasis. The process of angiogenesis involves a couple of factors and regulators such as therapeutic angiogenesis inhibitors and other endogenous factors. Based on current evidence, vitamin D is known to play a vital role in angiogenesis. The main source of receptor in the human body are the endothelial cells which help in the detection of vitamin D in the body. Vitamin D is also known to be absorbed by the vascular smooth muscle cells (VSMCs). Most of the tumor-derived endothelial cells are affected by 1,25 D3 (Vit. D) due to its proliferative effects. Vit. D can only induce these effects through the mediation of apoptosis and cell cycle arrest (Kisker, O., et al. 2003)
Many researchers have observed and proved in many long-term observation studies that vitamin D is known to play a vital role with respect to anti-angiogenic in numerous tumour model systems. However, many researchers also critic stating that vitamin D is also involved in the promotion of angiogenesis under most physiological conditions. Apart from the physiological changes observed in most studies, vitamin D has also known to affect the pathology of various cells including their physiological functions. Some of the main effects of vitamin D include motility, contractility, cell growth, vascular clarification, and VSMCs changes (Kisker, O., et al. 2003). Most of these physiological changes are of great importance in cardiovascular disease. In short, vitamin D is known to play a vital role in angiogenesis and vasculature. Further research on vitamin D and its potential across therapeutic areas would be of great importance. Lastly, preclinical data is known to prove that vitamin D anti-angiogenic effect and would play a key role in cancer therapy (Trump, D. L., Deeb, K., & Johnson, C. S. 2010).
Autophagy and mitophagy in angiogenesis
Based on current evidence, angiogenesis plays an important role in the prevention and recovery of peripheral vascular and ischemic heart disease. Based on the chronic ischemic and hypoxic conditions, researchers claim that there could be an increase in autopay which is in turn protective for such conditions. It is important to understand the role of autophagy in the process of angiogenesis. Thus, a clinical study was conducted to understand the potential role of autophagy and mitophagy in angiogenesis (Hu, Y.-L., et al. 2012).
In order to inhibit the effect of autophagy, the small interfering RNA (siRNA) and 3-Methyladenine (3-MA) were utilized against the ATG5 with the help of nutrient deprivation. The entire process was conducted with the help of cultured bovine aortic endothelial cells (BAECs). It was observed that angiogenesis was reduced due to the inhibition of autophagy by the siRNA and 3-MA. The reduction in angiogenesis was confirmed with the help of cell migration and tube formation in the assays of BAECs. On the other hand, the overexpression of ATG5 led to the induction of autophagy due to the increase of BAECs with respect to migration and tube formation. Further observations by the researchers also concluded that angiogenesis was induced by the impairment of vascular endothelial growth factor (VEGF) and the inhibition of autophagy ((Hamacher-Brady, A., & Brady, N. R. 2016).
It should also be noted that pro-angiogenesis factors such as integrin αV, VEGF, and platelet-derived growth factor are not altered due to autophagy. The activation of AKT phosphorylation is observed due to autophagy which would also increase the reactive oxygen species (ROS). The activation of AKT and the production of ROS decreased due to the inhibition of autophagy. However, there can be an increase in AKT activation in BAECs and cellular ROS production owing to overexpression of ATG5. Thus, autophagy and mitophagy play an important role in angiogenesis (Hamacher-Brady, A., & Brady, N. R. 2016).
References
Bao, P., Kodra, A., Tomic-Canic, M., Golinko, M. S., Ehrlich, H. P., & Brem, H. (2009). The Role of Vascular Endothelial Growth Factor in Wound Healing. The Journal of Surgical Research, 153(2), 347–358. http://doi.org/10.1016/j.jss.2008.04.023
Demidova-Rice, T. N., Durham, J. T., & Herman, I. M. (2012). Wound Healing Angiogenesis: Innovations and Challenges in Acute and Chronic Wound Healing. Advances in Wound Care, 1(1), 17–22. http://doi.org/10.1089/wound.2011.0308
Hamacher-Brady, A., & Brady, N. R. (2016). Mitophagy programs: mechanisms and physiological implications of mitochondrial targeting by autophagy. Cellular and Molecular Life Sciences, 73, 775–795. http://doi.org/10.1007/s00018-015-2087-8
Hu, Y.-L., DeLay, M., Jahangiri, A., Molinaro, A. M., Rose, S. D., Carbonell, W. S., & Aghi, M. K. (2012). Hypoxia-induced autophagy promotes tumor cell survival and adaptation to anti-angiogenic treatment in glioblastoma. Cancer Research, 72(7), 1773–1783. http://doi.org/10.1158/0008-5472.CAN-11-3831
Kisker, O., Onizuka, S., Becker, C. M., Fannon, M., Flynn, E., D’Amato, R., Pirie-Shepherd, S. (2003). Vitamin D Binding Protein-Macrophage Activating Factor (DBP-maf) Inhibits Angiogenesis and Tumor Growth in Mice. Neoplasia (New York, N.Y.), 5(1), 32–40.
Pung, Y. F., Sam, W. J., Hardwick, J. P., Yin, L., Ohanyan, V., Logan, S., Chilian, W. M. (2013). The role of mitochondrial bioenergetics and reactive oxygen species in coronary collateral growth. American Journal of Physiology - Heart and Circulatory Physiology, 305(9), H1275–H1280. http://doi.org/10.1152/ajpheart.00077.2013
Trump, D. L., Deeb, K., & Johnson, C. S. (2010). Vitamin D: Considerations in the Continued Development as an Agent for Cancer Prevention and Therapy. Cancer Journal (Sudbury, Mass.), 16(1), 1–9. http://doi.org/10.1097/PPO.0b013e3181c51ee6
Zou, M.-H., & Wu, Y. (2008). AMP-ACTIVATED PROTEIN KINASE ACTIVATION AS A STRATEGY FOR PROTECTING VASCULAR ENDOTHELIAL FUNCTION. Clinical and Experimental Pharmacology & Physiology, 35(5-6), 535–545. http://doi.org/10.1111/j.1440-1681.2007.04851
