Microvasculature

Introduction

The cutaneous microvasculature situated at the dermis just below the epidermis is the major instrument for skin microcirculation. The cutaneous vasculature has three major components: arteriole, venule, and lymphatic vessels ( ). In the sections that follow, the basic structures and common functions of blood vessels and lymphatic vessels are delineated. Having described these functional structures, we then discuss the roles of cutaneous microvasculature played in the inflammatory skin disease atopic dermatitis.

Cutaneous blood vessels: Structures

Since there is a close relationship between cutaneous blood vessels and cutaneous lymphatic vessels, the structures of cutaneous blood vessels are better depicted in conjunction with cutaneous lymphatic vessels. Fig. 12.1 illustrates a schematic picture of the structural proximity between these vessels ( ). More details on the structures of cutaneous blood vessels are discussed in other publications ( ).

The cutaneous microcirculation is organized into two horizontal plexuses. Plexus , derived from a Latin word meaning “braid,” denotes a branching network of blood vessels or nerves. The upper plexus is located just 1 to 1.5 mm below the stratum corneum, whereas the lower plexus is situated along the dermal-subcutaneous junction. Connecting the upper and lower plexuses are the pairing ascending arterioles and the descending venules. Arising from the upper horizontal plexus are the capillary loops. From an ultrastructural perspective, arterioles distinguish from capillaries and venules by the presence of an internal elastic lamina, capillaries are unique for their thin vascular wall containing pericytes (a special type cell of vessel wall) on the outer surface, and venules are characterized by their thicker vessel walls without elastic fibers. The papillary dermal arterioles have an outer diameter ranging from 17 to 26 μm and vessel wall with two layers of smooth muscle cells surrounding the endothelial cells at the lumen, and elastic fibers. As the arterioles move toward the capillary loop, their diameters, smooth muscle, and elastic fibers all reduce in caliber. When the vessels reach a size of 15 μm in outer diameter, the smooth muscles, which are identified by their dense bodies and myofilaments, are no longer present. At the point where the blood vessels turn into 10- to 12-μm outer diameter in size, all elastic fibers disappear, and this segment is now the beginning of arterial capillary. In the capillaries, pericytes, which also have contractile functions, replace smooth muscles and form tight junctions with endothelial cells. They have an important role in maintaining capillary integrity ( ). The next segment is venous capillary, which has one layer of pericytes around the vessel wall. Venous capillary then connects to the next segment of the postcapillary venule, which usually has an external diameter ranging from 18 to 23 μm at the papillary dermis level, a thicker wall of 3.5 to 5 μm, and two to three layers of pericytes around the vessel wall. The papillary dermal blood vessels are composed entirely of terminal arterioles, arterial and venous capillaries, and postcapillary venules, with the latter being the major component. The vessel sizes are generally larger at the lower part of the dermis. At the lower third of the dermis, arterioles and collecting venules can reach external diameter ranging from 40 to 50 μm, with vessel wall thickness ranging from 10 to 16 μm, and four to five layers of pericytes surrounding the vessel wall ( ).

Cutaneous blood vessels: Functions

One of the important functions of a cutaneous blood vessel is to provide nutrients to the skin. The capillary loops arise from the upper horizontal plexus, which is the primary avenue for nutrient delivery. The lower horizontal plexus, however, is responsible to supply life-sustaining substances for the hair bulbs, sweat glands, and other dermal glands ( ). The control of cutaneous blood flow is achieved by vasodilatation (increase) and vasoconstriction (decrease) through the smooth muscles directed by the sympathetic branch of the central nervous system ( ). Vasodilation, itself, also serves as an effective mechanism for thermal regulation (i.e., heat loss) ( ). The upper horizontal plexus acts as a thermal radiator ( ). Interestingly, physical exercise training can modify cutaneous microvascular reactivity to different stimuli ( ).

Another major function of cutaneous blood vessel is to provide immune support to the skin. As such, the microvascular system is always involved when there is an inflammatory event ( ). From a physiologic perspective, the postcapillary venules are the most important as they are the primary sites where inflammatory cells transmigrate from the vascular space into the target tissue sites. It is in this vessel segment that endothelial cells, in response to inflammatory signals, commonly develop intercellular gaps leading to increased vascular permeability ( ). Endothelial cells in the cutaneous blood vessel, when encountering appropriate triggers, such as stimulation by immunoglobulin-1 (IL1), tumor necrosis factor-α (TNF-α), or B-spectrum ultraviolet light, upregulate expressions on their cell surfaces of several adhesion molecules that facilitate the binding and the subsequent transportation of inflammatory cells out of the cutaneous blood vessels into the tissue location of the inflammatory targets. These adhesion molecules include intercellular adhesion molecule-1 (ICAM-1) (CD54), vascular cell adhesion molecule-1 (VCAM-1) (CD106), endothelial leukocyte adhesion molecule-1 (ELAM-1) (new term E-selectin, CD62E), and P-selectin (CD62P) ( ). The inflammatory cells, with the adhesion molecules such as cutaneous lymphocyte antigen (CLA), the very late antigen-4 (VLA-4, integrin α4β1) β1 subunit (CD29), or lymphocyte function-associated antigen-1 (LFA-1) α subunit (CD11a) expressed on their surfaces, can interact with ICAM-1, VCAM-1, or ELAM-1 and thus help to facilitate the movement into the tissue inflamed sites ( ). In addition, junctional adhesion molecules (JAMs), the proteins located at the borders of endothelial cells that take part in the final step of leukocyte extravasation, are also important for the transmigration of leukocytes from cutaneous blood vessels into the inflamed skin sites, although their expressions are unaltered by the inflammatory process ( ). Moreover, the expression of CD40 in endothelial cells, a costimulatory protein typically found in antigen-presenting cells, raises another possible role of cutaneous blood vessels in the skin inflammation ( ).

Another inflammation-related function of cutaneous blood vessels is documented in an animal model of wound healing. Mice lacking in both P- and E-selectins by genetic knockout showed a substantial reduction of inflammatory cell (neutrophils and macrophages) recruitment into the wounding site, resulting in impairment of wound closure ( ).

Cutaneous blood vessels can be examined in skin frozen sections by labeling with antibodies against common endothelial cell markers such as E-selectin or PAL-E ( ). Cutaneous blood vessels and blood flow can be assessed by different noninvasive methods, including laser-based techniques such as laser Doppler flowmetry or laser speckle contrast imaging (LSCI), and more recently by optical coherence tomography and photoacoustic imaging methodologies ( ).