Angiogenesis in PET studies

The process of new blood vessel growth by budding and sprouting from existing vessels in microvasculature (angiogenesis) is essential for tissue growth and regeneration, and it is strictly controlled by angiogenic stimulators and inhibitors. Vascular remodelling is the process where the arrangement and structure of existing vessels is changed through cell growth, apoptosis, migration, and production or degradation of the extracellular matrix (ECM).

Endothelial cells are the main building blocks of blood vessels. Angiogenesis is often triggered by tissue hypoxia. Hypoxia-inducible factor HIFα activates expression of vascular endothelial growth factor (VEGF). Hypoxia induces production of EPO which promotes angiogenesis in addition to increasing erythrocyte production. Inflammation, and metabolic and mechanical stress can also induce angiogenic process. Integrins are needed in endothelial cell growth, differentiation, adhesion, and migration. Perivascular cells (smooth muscle cells and pericytes) are recruited to the developing vessel, and when they have coated the endothelial cells of the vessel they stabilize it and inhibit further proliferation and migration of the endothelial cells, for instance by releasing sphingosine-1-phosphate and angiopoietin-1. Endothelial cells can release angiopoietin-2 (natural antagonist of angiopoietin-1) to promote angiogenesis. Platelets contain and release numerous growth factors and chemokines, regulating smooth muscle and endothelial cell proliferation and migration, recruiting bone marrow derived progenitor cells to form endothelial progenitor cells, and regulating apoptosis.

Angiogenic processes can be detected with numerous PET radioligands, including labelled integrin αvβ3 antagonists, ECM matrix metalloproteinase (MPP) inhibitors, and natriuretic peptides. Radiotracers for VEGF-receptor and endoglin have also been developed (Hong et al., 2014; Hendrikx et al., 2016). For instance, PET radiopharmaceuticals targeting endoglin have been used in treatment follow-up in peripheral artery disease animal models. Integrin αvβ3 targeting [18F]galacto-RGD PET is increased in myocardial infarct regions where perfusion is reduced (Makowski et al., 2021). PSMA has protease functions, and it may play a role in forming pro-angiogenic peptides.

The effects of angiogenesis inhibitors on tumour blood flow can be assessed using [15O]H2O PET (de Langen et al., 2008; Mammatas et al., 2021).

Arteriogenesis

Arteriogenesis is not induced by hypoxia and ischemia, but it is initiated in pre-existing collateral vessels. Increased perfusion pressure and pulsatile blood shear stress induces diametrical growth via transient inflammatory response, including growth factors and cytokines such as tumour necrosis factor α.

Vasculogenesis

Vasculogenesis is the de novo formation of blood vessels from progenitor cells, especially during embryogenesis. Endothelial cell precursors, angioblasts, associate to form primitive vessels; initially, only cord without the lumen is formed, followed by tubulogenesis (Xu & Cleaver, 2011).


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Literature

Cao Y (ed.): Angiogenesis in Adipose Tissue. Springer, 2013. doi: 10.1007/978-1-4614-8069-3.

Feige J-J, Pagès G, Soncin F (eds.): Molecular Mechanisms of Angiogenesis - From Ontogenesis to Oncogenesis. Springer, 2014. doi: 10.1007/978-2-8178-0466-8.

Figg WD, Folkman J (eds.): Angiogenesis - An Integrative Approach From Science to Medicine. Springer, 2008. doi: 10.1007/978-0-387-71518-6.

Haubner R, Beer AJ, Wang H, Chen X. Positron emission tomography tracers for imaging angiogenesis. Eur J Nucl Med Mol Imaging 2010; 37(Suppl 1): S86-S103. doi: 10.1007/s00259-010-1503-4.

Hendrikx G, Vöö S, Bauwens M, Post MJ, Mottaghy FM. SPECT and PET imaging of angiogenesis and arteriogenesis in pre-clinical models of myocardial ischemia and peripheral vascular disease. Eur J Nucl Med Mol Imaging 2016; 43: 2433-2447. doi: 10.1007/s00259-016-3480-8.

Hong H, Chen F, Zhang Y, Cai W. New radiotracers for imaging of vascular targets in angiogenesis-related disease. Adv Drug Deliv Rev. 2014; 76: 2-20. doi: 10.1016/j.addr.2014.07.011.

Marcu R, Zheng Y, Hawkins BJ. Mitochondria and angiogenesis. Adv Exp Med Biol. 2017; 982: 371-406. doi: 10.1007/978-3-319-55330-6_21.

Mehta JL, Dhalla NS (eds.): Biochemical Basis and Therapeutic Implications of Angiogenesis. Springer, 2013. doi: 10.1007/978-1-4614-5857-9.

Ribatti D: Inflammation and Angiogenesis. Springer, 2017. 10.1007/978-3-319-68448-2.

Salajegheh A: Angiogenesis in Health, Disease and Malignancy. Springer, 2016. doi: 10.1007/978-3-319-28140-7.

Sweeney M, Foldes G. It takes two: endothelial-perivascular cell cross-talk in vascular development and disease. Front Cardiovasc. 2018; https://doi.org/10.3389/fcvm.2018.00154.



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Updated at: 2023-01-15
Created at: 2017-09-25
Written by: Vesa Oikonen