Vascular Endothelial Cells: Heterogeneity and Targeting Approaches

Abstract

Forming the inner layer of the vascular system, endothelial cells (ECs) facilitate a multitude of crucial physiological processes throughout the body. Vascular ECs enable the vessel wall passage of nutrients and diffusion of oxygen from the blood into adjacent cellular structures. ECs regulate vascular tone and blood coagulation as well as adhesion and transmigration of circulating cells. The multitude of EC functions is reflected by tremendous cellular diversity. Vascular ECs can form extremely tight barriers, thereby restricting the passage of xenobiotics or immune cell invasion, whereas, in other organ systems, the endothelial layer is fenestrated (e.g., glomeruli in the kidney), or discontinuous (e.g., liver sinusoids) and less dense to allow for rapid molecular exchange. ECs not only differ between organs or vascular systems, they also change along the vascular tree and specialized subpopulations of ECs can be found within the capillaries of a single organ. Molecular tools that enable selective vascular targeting are helpful to experimentally dissect the role of distinct EC populations, to improve molecular imaging and pave the way for novel treatment options for vascular diseases. This review provides an overview of endothelial diversity and highlights the most successful methods for selective targeting of distinct EC subpopulations.

Keywords: endothelial cell; endothelial heterogeneity; endothelium; vascular endothelial cell; vascular targeting; vasculature.

Figure 1

Three main types of capillary EC. (a) A tight continuous endothelium with a continuous basement membrane can be found in the capillaries of organs such as the brain, the lung and the heart. Molecules can pass the continuous endothelium by tightly regulated transcytosis. (b) The endothelium of the kidney and the choroid plexus is fenestrated and allows for diffusion of fluids and small molecules. (c) The capillary endothelium of liver and bone marrow is discontinuous with intercellular gaps and a discontinuous basement membrane, enabling free exchange of molecules. This figure contains artwork components of Servier Medical Art.

Figure 2

EC heterogeneity in response to stress. (a) During the acute inflammatory response, increased intracellular calcium activates eNOS and leads to vasodilation. Attracted neutrophils transmigrate through the endothelial layer. Upregulation of adhesion molecules and pro-inflammatory cytokines leads to further leukocyte recruitment. The attraction of either Th1 or Th2 cells determines the further inflammatory process. During inflammation, some organs, such as brain, lung and heart preferentially express certain adhesion molecules, cytokines or transporters. (b) The response to hypoxia shows some similarities to the inflammatory response. Intracellular calcium increases and, in most organs, leads to vasodilation. The small vessels of the kidney and the lung conversely react with vasoconstriction. Low oxygen and low pH lead to excessive amounts of calcium, resulting in cell damage and caspase-mediated apoptosis. Further damage is induced by reactive oxygen species (ROS) upon reperfusion. Increased expression of cell adhesion molecules and pro-inflammatory cytokines leads to leukocyte recruitment and fosters an inflammatory phenotype. (c) The tumor endothelium is highly angiogenic and appears chaotic. The extracellular matrix is rearranged and the endothelial layer is leaky, allowing the transmigration of tumor-associated macrophages and other leukocytes to take place. Tumor ECs express VEGFR-2, pro-inflammatory cytokines, cell adhesion molecules, hypoxia-induced factors (HIFs) and matrix metalloproteinases. Tumor ECs are highly diverse, even within the same cancer entity. This figure contains artwork components of Servier Medical Art.

Figure 3

Different approaches of selective EC targeting. Antibodies, nanobodies and phage-selected peptides, as well as different kinds of viral vectors, can be used to specifically target distinct EC populations. Possible applications and limitations of the different targeting approaches are indicated. This figure contains artwork components of Servier Medical Art.