Under-Recognized Significance of Endothelial Heterogeneity: Hemostasis, Thrombosis, and Beyond

It is well established that the endothelium plays an important role in the regulation of physiological functions and in the pathogenesis of many diseases. Endothelium is composed of many diverse phenotypes with a dynamic structure that responds both spatially and temporally to changes in its extracellular environment. Different diseases affect the endothelium at specific locations. The significance of these multiple facets of the endothelium is often overlooked. In this issue of Seminars in Thrombosis and Hemostasis, we have assembled a series of articles written by contributors selected for their respective expertise in the study of the endothelium. These articles address our current understanding of how and why endothelial phenotypes differ in space and time, and how this information can help us both clinically and in future research.

To begin with, Dyer and Patterson describe the appearance of endothelial heterogeneity in embryonic development. They indicate how a series of signaling pathways orchestrate the migration of the developing endothelial cells to their specific organs, along with acquiring different functions. This is followed by a detailed description of site-specific morphology of the endothelium by Tse and Stan.

Next, Molema reviews functional heterogeneity of the endothelium in response to inflammatory mediators and discusses how spatial and temporal differences in endothelial cell activation may be leveraged for therapeutic gain.

In addition to biochemical signals, the endothelium is highly responsive to biomechanical forces. As reviewed by Davies et al, flow characteristics vary across the endothelium in accordance with differences in the underlying geometry of the vascular tree. These authors discuss how flow mediates the set point of the endothelium and affects its subsequent response to inflammatory states, including risk factors for atherogenesis and valvular dysfunction.

Aird points out that any consideration of the mechanisms of endothelial heterogeneity must take into account both proximate and evolutionary causation. He concludes that endothelial heterogeneity arises from a complex interplay between the genome and the environment, operating at both population and organismal levels across a broad spectrum of time. He further posits that a mismatch between the genome or the epigenome and the environment is an important determinant of human vascular disease.

The role of the endothelium in hemostasis and thrombosis is reviewed by Kwaan and Samama. They provide new insights into the mechanisms underlying site-specific thrombotic complications in some diseases and local hemorrhagic complications in others.

Ochoa and colleagues then review evidence for the existence of microheterogeneity at the level of the pulmonary endothelium, including anatomical and physiological differences between pulmonary arteries, veins, and capillaries. As an example, they focus on vascular-segment-specific regulation of von Willebrand factor and P-selectin in health and disease.

As subsequently reviewed by Khankin et al, the placenta provides a fascinating example of a vascular bed that is genetically heterogeneous, consisting of a hybrid between fetal and maternal blood vessels and between two different vascular lining cells, the trophoblast and endothelial cell. They discuss how these unique features contribute to the development of preeclampsia and intrauterine growth restriction.

It has long been recognized that tumor blood vessels are structurally and morphologically distinct. More recent evidence indicates that tumor endothelial cells display molecular and functional heterogeneity. Nagy et al discuss these differences and provide new insights into their therapeutic implications.

With a better understanding of organ-specific and vascular bed–specific characteristics of endothelium, new drug designs aimed at local drug delivery are now possible. The prospective agent would have the attraction of being more efficacious at the pathological lesion but with less toxicity to the rest of the body. As reviewed by Carnemolla and colleagues, exciting strategies are evolving for the delivery of fibrinolytic agents and of antioxidants to the pulmonary vasculature.

From a molecular standpoint, the endothelium expresses a rich repertoire of luminal proteins that vary from one vascular bed to another. Pasqualini et al describe how these “vascular zip codes” may be exploited for site-specific drug delivery and molecular imaging.

In contrast to the endothelial cells lining blood vessels, far less is known about lymphatic endothelial cells. Lee and colleagues review the biology of lymphatic endothelium, with a focus on its phenotypic heterogeneity and plasticity.

We thank the authors for these most interesting contributions. We also hope that this collation of articles, reviewing different aspects of the endothelium within a single issue of Seminars in Thrombosis and Hemostasis, will provide valuable resource material for readers from many disciplines.