The endothelium is the layer of endothelial cells lining the inner surface of blood vessels, which span the entire body and ensure the distribution of blood throughout the organism. It is estimated that the human body contains a staggering 100,000 km of blood vessels, more than twice the earth’s circumference. Therefore, a bacterium reaching the circulation is engaged in a network of huge proportions. Moreover, a pathogen traveling through the circulatory system does not encounter a homogeneous environment, as an important feature of the vascular network is its diversity. Although endothelial cells are present in all vessels, the organization of the vessel wall, which is formed by three layers—the tunica intima, media, and adventitia (from the vessel lumen outward)—is different among different vessel types and different organs. Vessels can be first differentiated by the complex extracellular matrix layers surrounding them. For instance, elastic arteries such as the aorta are surrounded by 50 elastic layers, providing them with unique mechanical properties. Second, the cellular content is also different according to vessel type; the walls of arteries and veins contain a layer of smooth muscle cells that gives them the capacity to relax or constrict in response to vasoactive molecules. An additional level of complexity in the network stems from the fact that larger vessels, veins or arteries, are themselves vascularized by smaller vessels, the vasa vasorum.