Vasculogenesis and Angiogenesis

Introduction

In light of the premise of angiogenesis as an organizing principle, it is not surprising that drugs that have been developed to modulate angiogenesis can be effective to treat apparently dissimilar conditions. For example, a blinding disease like wet age-related macular degeneration that affects primarily older individuals appears to have little in common with colorectal or lung cancer, yet these diseases may be treated using the same anti-angiogenesis therapies.

Organizing principles also enable discoveries in one field to illuminate understanding in other fields. For instance, the study of large populations suffering from cerebral cavernous malformations, an inherited condition commonly associated with brain hemorrhage, uncovered a previously uncharacterized cell signaling mechanism mediating vascular development and stability in the brain.

In the first section of this chapter, we briefly review our current understanding of the key principles governing vascular development. This discussion should familiarize the reader with the main cellular and molecular players involved in the process of vessel formation, maturation and remodeling, which are key for understanding the pathological conditions introduced thereafter. The coverage in this section is not intended to be comprehensive, as the main goal is to focus on molecular aspects of pathologic angiogenesis. We do, however, cite key review articles that the reader will find useful to read further on this topic.

The second part of this chapter will cover conditions that arise from abnormal vascular development with an emphasis on the genetics and molecular basis of these diseases. These include vascular malformations, hemangiomas, hereditary hemorrhagic telangiectasia, and cerebral cavernous malformations. Some of these conditions do not present in the newborn but instead become apparent or progress over time.

The third part of this chapter includes a discussion of the role of angiogenesis in the tissue response to disease for very prevalent conditions, including cancer, brain ischemia, myocardial infarction, critical limb ischemia, and neovascular eye disease. Here we emphasize the promise of angiogenesis as a therapeutic target for ischemic conditions.

Vascular Development

The development of the vascular system involves the processes of vasculogenesis and angiogenesis. Vasculogenesis is defined as the de novo formation of a blood vessel from angioblasts giving rise to the heart, the first primitive vascular plexus, and the yolk sac circulation. Angiogenesis involves the expansion of the vasculature from existing vessels through sprouting and intussusceptive microvascular growth ( Figure 10.1 ). The regulation of vascular development was first described in the chick in the 1930s where the phases of extraembryonic and embryonic vascularization were first documented. These initial studies were largely descriptive and for decades the molecular bases of vascular development remained unknown.

The advent of mouse models of targeted gene deletion allowed the identification of specific gene products responsible for the process of vascular development. Accordingly, a large number of genes have been shown to be critical to proper vascular development and are the target of mutations associated with human disease.

Among the most dramatic vascular defects are seen with the knockout of vascular endothelial growth factor (VEGF; also known as vascular permeability factor, VPF) in mice. Loss of a single allele of VEGF was shown to lead to embryonic lethality at embryonic day (E) 9.5 with nearly complete lack of aorta and the absence of yolk sac vasculature. The fact that heterozygous deletion yields a phenotype nearly as complete as homozygous knockout points to the importance of dosage in the effects of VEGF. Not surprisingly, targeted disruption of VEGFR2, the primary signaling receptor for VEGF, closely phenocopies the loss of VEGF. Interestingly, loss of a second VEGF receptor VEGFR1 does not lead to a similar disruption of vascular development but rather results in an over-proliferation of vascular endothelial cells. This observation has led to the suggestion that VEGFR1 may act as a ‘decoy’ for VEGF, sequestering soluble VEGF and thus preventing its mitogenic action on the endothelium. VEGF misregulation is central to vascular pathology during development and in adult tissues as discussed later.

Once a large vessel (such as the aorta) or a primitive capillary plexus is formed, the vessel undergoes a series of steps that lead to a mature, stable state. For large vessels, this consists of the recruitment of mesenchymal cells that are induced to differentiate into smooth muscle cells and then proliferate to generate vessels of appropriate wall thickness e.g. artery vs. vein. At the level of the microvasculature, immature capillary tubes similarly recruit mesenchymal cells – with the primary difference being that pericytes, by definition, never fully cover the abluminal surface of the capillary nor do they overlap one another. In spite of the significant structural difference between the largest arteries and the microvasculature, the same molecules and mechanisms are used in the process of their remodeling. Tissue culture studies followed by targeted gene deletions have revealed the complexity of the remodeling and stabilization process. Using cocultures of vascular endothelial cells and undifferentiated mesenchymal cells, proliferating endothelial cells have been shown to release platelet-derived growth factor B (PDGF-B) that acts as both a chemoattractant and mitogen for the smooth muscle cell precursors. Once the mesenchymal cells contact the endothelium, the mesenchymal cells are induced to differentiate to a smooth muscle cell/pericyte fate.

Developmental Abnormalities