These differences manifest in variable permeability, responsiveness and biosynthesis. ECs differ morphologically, physiologically and phenotypically along the vascular tree, between arteries and veins, arterioles and venules, even within capillaries of the same vascular beds and between different organs within the body. Vascular ECs adapt to their specific niche in the context of the individual organs by highly specialized functions (e.g., blood–brain barrier, glomeruli in the kidney, or sinusoids in the liver). A recently published comprehensive single-cell transcriptome atlas of murine ECs reveals the vast diversity of vascular EC on the transcriptional level alone. Indeed, blood vessels of different compartments of the organism express specific markers. Even the most common EC markers, such as CD31 and the von Willebrand Factor (vWF), are expressed in a heterogeneous pattern along different EC populations. Although all blood vessels share common functions, such as oxygen and metabolite transport, not all blood vessels and especially not all ECs are equal. Changes in the glycocalyx have also been linked to the treatment response in sepsis. Disruption or dysfunction of the glycocalyx has been associated with diseases such as diabetes, chronic kidney disease, inflammatory condition, sepsis, hypernatremia, hypervolemia and ischemia/reperfusion injury. Some of the targeting agents discussed in this review utilize components of the endothelial glycocalyx as primary attachment receptors. The luminal surface of all vascular endothelial cells is covered by the endothelial glycocalyx, which comprises membrane-bound, negatively charged proteoglycans, glycolipids and glycosaminoglycans, thereby contributing to mechanotransduction, cell signaling and adhesion of blood cells and pathogens. Indeed, this unique cell layer acts as an endocrine organ and constitutes a selectively permeable barrier between extra- and intravascular compartments by controlling the exchange of compounds between the bloodstream and the surrounding tissue in an organ-specific manner. Therefore, the vascular endothelium can be considered the largest organ in the human body. Their cumulative surface area is estimated to be approximately 1000 m 2. The vascular endothelium is a heterogenous monolayer of highly specialized cells, the endothelial cells (ECs), that face the luminal side of all blood vessels and represent the first barrier for all molecules, cells or pathogens circulating in the bloodstream. This review provides an overview of endothelial diversity and highlights the most successful methods for selective targeting of distinct EC subpopulations. 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. 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. 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. The multitude of EC functions is reflected by tremendous cellular diversity. ECs regulate vascular tone and blood coagulation as well as adhesion and transmigration of circulating cells. Vascular ECs enable the vessel wall passage of nutrients and diffusion of oxygen from the blood into adjacent cellular structures. Forming the inner layer of the vascular system, endothelial cells (ECs) facilitate a multitude of crucial physiological processes throughout the body.
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