Vascular development and disorders: Molecular analysis and pathogenic insights

Abstract

Blood vessels are among the first organs to develop during embryogenesis and are essential for organogenesis and nutrition of the embryo. Although formation of blood vessels most actively occurs during embryonic development, tissue vascularization proceeds after birth in the retina, in the heart, and, cyclically, in the reproductive organs. In addition, abnormal vessel growth importantly contributes to the pathogenesis of several disorders with high morbidity and mortalitiy. Excessive vessel growth has been implicated in the pathogenesis of retinopathies, cancer and inflammation. In contrast, insufficient vessel growth may lead to tissue ischemia and failure. Although formation of new blood vessels has typically been associated with endothelial cells, the periendothelial mural pericytes (smaller vessels) or smooth muscle cells (larger vessels) are equally important for normal and pathological vessel formation. Indeed, a developing network of endothelial tubes that is not surrounded by mural cells is fragile and prone to rupture, remains susceptible to hypoxic regulation, fails to become remodeled, is unable to sustain proper circulation, and cannot adapt to changes in physiological demands of blood supply. Notably, vascular growth does not always involve formation of new capillaries, but may depend on remodeling of pre-existing arteriolized vessels, such as during collateral growth in the myocardium. The importance of periendothelial cells is further deduced from the pathological loss of smooth muscle cells in atherosclerotic vessels (leading to media necrosis), or from the pericyte drop out in diabetic retinal vessels, which renders them prone to aneurysmal rupture. Conversely, accumulation of smooth muscle cells contributes to atherosclerotic plaque growth and arterial stenosis. Recent studies have highlighted the importance of endothelial periendothelial cell crosstalk during normal and pathological blood vessel formation. Accordingly, integrated research into the molecular mechanisms that regulate the development and function of both endothelial and pericyte/smooth muscle cells has become a major focus in vascular biology. A number of candidate molecules (growth factors, matrix component, adhesion molecules, and proteinases) have been identified that stimulate or inhibit these processes. Recently, remarkable progress in their molecular analysis has been achieved through targeted manipulation of the mouse genome. Their role will be discussed in this review.