The Mechanics of Blood Vessel Growth

Abstract

Blood vessel growth is pivotal in various processes in health and disease; examples are embryogenesis, inflammation, wound healing, cardiac ischemia, diabetic retinopathy, and tumor growth. The latter, in particular, has been the subject of extensive studies due to the high mortality rates associated with oncologic diseases. However, and despite the continuous efforts by the scientific community, both the genomic characterization of tumors (Maley et al., 2006; Wood et al., 2007) and the main physical mechanisms driving their development (Araujo & McElwain, 2004) are currently a matter of debate. These efforts have been greatly enriched through an interdisciplinary approach. Physics, Mathematics and computer simulation and modeling have currently a key role in the research of tumor growth in general and vessel development in particular. The approach of mathematicians and physicists provides remarkable new ways of looking into Biology: starting the modeling from basic principles, the fundamentals of the problem can be tested and understood. The relevance of blood vessel growth for tumor development is well documented (Figg & Folkman, 2008). In the early stages of development, the growth of a solid tumor is limited in size due to cell apoptosis at its core by lack of nutrients. In simple terms, the acquisition of nutrients at the boundary is not able to meet the needs of the inner cells. This, in addition to a problem of confinement of the inner cells (the fast growth does not allow them to migrate) produces the so called core necrosis inside the tumor. When this stationary non-threatening stage is reached, malignant tumors adapt to the environment and undergo an active search for the nutrients they need to survive and proliferate. This can be achieved by releasing factors, such the Vascular Endothelial Growth Factor (VEGF), which drive nearby vessels to extend new branches in the direction of the tumor, through a process called angiogenesis, providing it with nutrients (Figg & Folkman, 2008). Hence, understanding angiogenesis is essential to the potential control of the blood delivered to a neoplasic tissue in order to prevent and contain its development and metastatic colonies. In fact, though hyper-vascularization is not a requirement for a tumor to metastasize (Mateus et al., 2009), the cells of a densely vascularized tumor have a much higher facility in entering the blood circulation. During the last decade cancer therapies based on anti-angiogenic factors have been a focus of interest. However, this type of treatment has not given the expected results (Mayer, 2004) and recently, the concept of normalization of tumor vasculature has been proposed (Jain, 2005), where it is suggested that certain anti-angiogenic agents can transiently normalize 9