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Human Skin Microcirculation

Jean‐Luc Cracowski, Matthieu Roustit

10.1002/cphy.c190008

Source: Volume 10, Issue 3, July 2020

Published online: July 2020

Full Article on Wiley Online Library



Abstract

The anatomy and physiology of the microcirculation in human skin are complex. Normal cutaneous microcirculation is organized in two parallel plexuses with capillary loops extending perpendicularly from the superficial plexus. The physiological regulation of cutaneous microcirculation includes specific sympathetic activation, which causes vasoconstriction through the release of norepinephrine, neuropeptide Y, and ATP. A sympathetic cholinergic system is mainly involved in vasodilation through the co‐transmission of acetylcholine, vasoactive intestinal peptide, and pituitary adenylate cyclase‐activating peptide. Sensory nerves play a major role through the release of calcitonin gene‐related peptide and substance P. Endothelium‐dependent vasomotion implicates nitric oxide, prostacyclin, endothelium‐dependent hyperpolarizing factors, and endothelin. Myogenic response also plays a role and explains why autoregulation is weak but exists in glabrous human skin. Variations in skin blood flow result from highly complex interactions between these mechanisms. In this article, we will detail the anatomy, physiology, and current methods of exploring the human microcirculation. We will further discuss the part played by cutaneous microvascular impairment in the pathophysiology of cardiovascular and metabolic diseases, or diseases more specifically affecting the skin. © 2020 American Physiological Society. Compr Physiol 10:1105‐1154, 2020.

Figure 1. Figure 1. The anatomy of the skin's microcirculation. This includes the deep horizontal plexus (E) parallel to the skin surface at the derma‐hypoderma interface from which ascending arterioles (C) rise and form a superficial plexus (B) protruding into the derma. Capillary loops (A) are perpendicular to the skin's surface except in specific regions such as nail folds. Arteriovenous anastomoses (D) traverse the superficial plexus and are mostly present in glabrous skin such as the palm of the hands and the sole of the feet. They can have either a glomerular or elongated shape. Other skin features include sweat glands (green) and hair follicles.
Figure 2. Figure 2. Section through the palmer side of a surgically removed finger (supernumerary digit of an 18‐year‐old male) studied by corrosion casting. One can clearly distinguish the papillary layer from which capillary loops arise (i), the subpapillary plexus (ii), the reticular layer (iii), and the hypodermal layer (iv), together with the ascending arterioles (A) and descending venules (B), 400. The regular linear disposition of the capillary loops follows the pattern of the fingerprint lines.
Figure 3. Figure 3. Section through the hypodermal layer of the palmer side of a finger studied by corrosion casting showing an arteriovenous anastomosis located between an arteriole (a) and a venule (v) exhibiting a glomerular‐shaped body 400. Direct connection arteriovenous anastomoses have been described in humans. Endothelial cell nuclei slightly protrude from the vascular lumen as seen on the cast (white arrow).
Figure 4. Figure 4. Forearm blood flow recorded simultaneously by venous occlusion plethysmography in both arms, of the same individual, one of which was pretreated using epinephrine whole forearm iontophoresis (treated arm) and the other used as a control (untreated arm). The difference between them is plotted as absolute forearm skin blood flow. Skin blood flow plotted against muscle blood flow gives a broad spread showing that even when recorded simultaneously in the same territory there is considerable variability between skin and skeletal muscle blood flow 91.
Figure 5. Figure 5. Relationship between capillary pressure in the hand and the distance of the hand below the heart. The subject was initially supine, then sat up and then stood 293. As the extremity of the hand was lowered, the arterial and venous pressures rose linearly with hydrostatic load while capillary pressure rose far less in comparison.
Figure 6. Figure 6. The simultaneous effect of Valsalva's maneuver (respiratory movements recorded on the upper tracing) on intra‐arterial blood pressure (bottom tracing) and sympathetic activity from a median nerve fascicle in skeletal muscles (middle tracing). Valsalva's maneuver is responsible for the initial rise and subsequent drop in systemic blood pressure, and a simultaneous increase in sympathetic activity clearly seen during the drop in blood pressure. Adapted, with permission, from Delius W, et al., 1972 114.
Figure 7. Figure 7. The simultaneous effect of Valsalva's maneuver (respiratory movements recorded on the upper tracing) on intra‐arterial blood pressure (bottom tracing) and sympathetic activity in the skin (middle tracing). In contrast to the skeletal muscles (Figure 6), Valsalva's maneuver had little or no impact on the sympathetic activity of glabrous skin despite an initial rise, followed by a drop in systemic blood pressure 112.
Figure 8. Figure 8. Schematic representation of skin vasodilator pathways. The skin microcirculation is subject to complex neurogenic regulation. First during heat challenges the sympathetic cholinergic system is implicated in the release of acetylcholine, vasoactive intestinal polypeptide (VIP) and pituitary adenylyl cyclase cyclase‐activating peptide (PACAP). Secondly, sensory nerves play a major role in different reflexes through the release of calcitonin gene‐related peptide (CGRP) and substance P, and probably neurokinin A. The endothelium also plays an important role through the release of nitric oxide (NO), prostacyclin (PGI2), and endothelium‐derived hyperpolarizing factors (EDHF) such as the epoxyeicosatrienoic acids (EETs). Pericytes (represented here as the green cell) are frequently found and play a major role in the regulation of vascular tone and tissue regeneration. Different transient receptor potential (TRP) channels are expressed on endothelial cells, smooth muscle cells, and neurons and mediate a wide range of physiological responses. AC, adenylyl cyclase; Ach, acetylcholine; ADM, adrenomedullin; BK, bradykinin receptor B2; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; CLRC/RAMP, calcitonin receptor‐like receptor/receptor activity‐modifying protein; COX, cyclooxygenases; CYP, cytochromes P450; eNOS, endothelial nitric oxide synthase; EP2, prostaglandin EP2 receptor 2; EP4, prostaglandin EP2 receptor 4; GPR68, ovarian cancer G‐protein‐coupled receptor 1; IP, prostacyclin receptor; H1, histamine H1 receptor; HETE, hydroxyeicosatetraenoic acids; IR, insulin receptor; LOX, lipoxygenases; M3, muscarinic acetylcholine receptor 3; MRP4, multidrug resistance‐associated protein 4; NK1, neurokinin 1 receptor; P1A1‐3, A‐type purinergic receptors 1, 2, and 3; P2Y12, P‐type purinergic receptor Y12; PECAM‐1, platelet endothelial cell adhesion molecule 1; PGE2, prostaglandin E2; PGI2, prostacyclin; PIEZO‐1, piezo type mechanosensitive ion channel component 1; PKA, protein kinase A; PKC, protein kinase C; PLA2, phospholipase A2; PPAR, proliferator peroxisome‐activated receptor; RYR, ryanodine receptors; TRP, transient receptor potential channel; VEGFR, vascular endothelial growth factor; VPAC, vasoactive intestinal peptide receptor.
Figure 9. Figure 9. Schematic representation of skin vasoconstrictor pathways. The skin microcirculation is under the influence of neurogenic regulation, represented by the sympathetic adrenergic pathway through the release of norepinephrine (NE) with neuropeptide Y (NPY) and ATP co‐transmission. Cold‐induced norepinephrine‐dependent vasoconstriction is mediated primarily by α2 adrenergic receptors and their mobilization to the cell membrane, depending on the activation of the RhoA‐rho kinase pathway. Endothelin‐1 (ET‐1) induces long‐lasting ETA‐mediated vasoconstriction but also triggers an ET‐A dependent axon reflex in the surrounding area. cAMP, cyclic adenosine monophosphate; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; AT1, angiotensin receptor type 1; ECE, endothelin converting enzyme; eNOS, endothelial nitric oxide synthase; P2X1, P2Y12, P‐type purinergic receptor X1; PLA2, phospholipase A2; PLC, phospholipase C; ROCK, rho‐associated protein kinase; ROS, reactive oxygen species; TRP, transient receptor potential.
Figure 10. Figure 10. Representative experiment (in one subject) in which finger blood flow was monitored using venous occlusion air plethysmography. Blood flow was recorded at thermoneutrality (room temperature 25°C) and during a whole‐body cooling stress (1 h at 20°C room temperature). Phenylephrine, an α1 adrenergic receptor agonist, produced a dose‐dependent decrease in finger blood flow. Clonidine, an α2 adrenergic receptor agonist was more potent (not shown here). Prazosin, an α1 adrenergic receptor antagonist had no effect on basal blood flow but reversed the phenylephrine‐induced reduction in blood flow. During cold exposure, the same dose of prazosin produced only a slight increase in blood flow (mean flow rose from 7.7 to 11.7 mL/min/100 mL) while yohimbine, an α2 adrenergic receptor antagonist increased finger blood flow by the same amplitude seen at thermoneutrality 88. This experiment shows that while adrenergic α1 receptors are present and can respond to the intra‐arterial injection of phenylephrine, the cold‐induced finger vasoconstriction is mediated primarily by alpha‐2 adrenergic receptors.
Figure 11. Figure 11. In this representative experiment, forearm blood flow was recorded using water‐filled venous‐occlusion plethysmographs. The authors assumed that the increased blood flow in the forearm during whole‐body heating was mostly due to skin vasodilatation. Forearm blood flow was continuously measured in neutral thermal conditions (subjects placed in a 34°C bath) and during whole‐body heating (where the bath temperature was raised to reach an oral temperature of 38°C) and subsequent cooling. Cutaneous nerves were anesthetized in one arm (lidocaine injections, black rectangles) and not in the contralateral arm (saline injections, open rectangles). In the control arm, forearm blood flow rose, while nerve blockade blunted the heat‐induced vasodilatation 129. This experiment suggests that during whole‐body heating, microcirculation in the forearm skin is mostly regulated by an active vasodilator mechanism and not by the release of a vasoconstrictor.
Figure 12. Figure 12. Effect on skin blood flow of two concentrations of substance P (top) and CGRP (bottom) infused during 30 min (black bar) through microdialysis fibers placed 660 μm deep into the human skin with and without concomitant 5 μM l‐NAME (a NO synthase inhibitor) infusion. First, it is worth noting that substance P induced an early rise in skin blood flow mediated by NK1 receptors. However, this effect was transient, with skin blood flow decreasing while substance P was still being infused, as a consequence of internalization and subsequent desensitization of NK1 receptors. This early and transient vasodilatation totally contrasts with the effect of CGRP that produced delayed onset and a sustained plateau far beyond the end of the injection. Secondly, the inhibition of nitric oxide production provoked a reduction in baseline blood flux, and an important inhibition of the substance P induced vasodilatation, showing that the substance P effect was partly nitric oxide dependent while its effect on CGRP induced vasodilatation was smaller. Thirdly, substance P induced protein extravasation, which was partly nitric oxide dependent, while CGRP did not (data not shown in this figure) 268.
Figure 13. Figure 13. Prostacyclin was infused at increasing concentrations through four microdialysis fibers in nine healthy young males. One fiber was used as control, one was perfused with LNNA, a nonspecific NO‐synthase inhibitor, one was perfused with the nonspecific KCa channel blocker tetraethylammonium, and one with a combination of both. Both NO synthase and KCa channel blockade decreased the amplitude of prostacyclin vasodilatation, and their addition potentiated their inhibitory effect. This indicates that there is accumulative interaction between the three major endothelial pathways in the human skin, that is, the prostacyclin, nitric oxide, and EDHFs pathways 161.
Figure 14. Figure 14. Individual recordings of hand and forearm blood flow, in ordinate (mL/100 mL/min) using venous occlusion plethysmography before (R for resting) and after increasing concentrations (in μg) of acetylcholine were injected over one min into the brachial artery 119. The data show that the muscarinic receptor agonist acetylcholine was able to induce a concentration‐dependent increase in forearm and hand blood flow, and confirms that muscarinic acetylcholine receptors are present in the microvasculature of the forearm and hand. The apparent reduced efficacy of acetylcholine observed in the hand is due to its rapid degradation by cholinesterases.
Figure 15. Figure 15. Injection of 4 mg of acetylcholine into the brachial artery increased hand skin blood flow during approximately 15 min. In contrast, injection of 0.8 mg atropine had no immediate effect but subsequently prevented acetylcholine vasodilatation 45 min later 168. This shows that muscarinic acetylcholine receptors are present within the hand vascular walls despite the fact that acetylcholine was not released in the vicinity under thermoneutral conditions.
Figure 16. Figure 16. (A) Confocal fluorescence microscopy of human abdominal skin incubated with a NO fluorochrome and then irradiated with ultraviolet A corresponding to natural sunlight exposure at noon on a sunny day. White scale bar: 100 μm. Most fluorescence can be seen within the epidermis when compared with (B) a near contiguous section of hematoxylin and eosin‐stained skin, (C) the addition of l‐NMMA had no effect on ultraviolet A‐induced fluorescence, and (D) the addition of a NO scavenger prevented the any increase in fluorescence 302. This shows that apart from in the vascular endothelium, nitric oxide can also be produced by the epidermis through a non‐NO‐synthase pathway, and induces vasodilatation.
Figure 17. Figure 17. Representative laser Doppler flowmetry tracings of local skin hyperemia expressed as a percentage of maximal skin blood flow during infusion of 50 mM sodium nitroprusside. The classical initial axon reflex dependent peak is followed by a long‐lasting plateau. Most of the plateau vasodilatation was reversed when the NO‐synthase inhibitor l‐NAME was injected intradermally at 40 min (A). When l‐NAME was infused during local heating (B), plateau skin blood flow and to a lesser extent the peak decreased in amplitude 331, showing the major contribution of nitric oxide to the plateau phase.
Figure 18. Figure 18. Intradermal injections of endothelin‐1 induced vasoconstriction on the volar face of human forearm (white circles) and vasodilation in the area surrounding the injection site (A), that was blunted after prolonged pretreatment with capsaicin ointment (B) 503. Therefore, in human skin, endothelin‐1 induces long‐lasting ETA‐receptor mediated vasoconstriction but also triggers an ETA‐receptor dependent axon reflex in the surrounding area.
Figure 19. Figure 19. Palm and forearm cutaneous vascular conductance recorded at baseline and during the last 5 min of a 15 min Valsalva's maneuver during which blood pressure decreased. To avoid the confounding role of sympathetic activity to skin, experiments were performed after ganglionic blockade through intravenous injection of trimethaphan, a short‐acting competitive antagonist of the nicotinic acetylcholine receptors, and compared with control conditions 127. Ganglionic blockade was confirmed because trimethaphan abolished the increase in heart rate during Valsalva's maneuver. Trimetaphan unmasked an increase in skin conductance in both the palms and the forearm showing that these skin vascular beds are capable of dilating in response to pronounced drops in perfusion pressure so as to maintain constant blood flow.
Figure 20. Figure 20. Representative images of nail fold videocapillaroscopy with a magnification of 100×. (A) Normal pattern showing homogenous distribution of capillary loops. (B) Pattern observed in a patient with systemic sclerosis, showing disorganized enlarged/giant capillaries 387.
Figure 21. Figure 21. First in vivo tracing in 1975 of the variation of the skin laser Doppler flow signal over time. Forearm ischemia was performed by inflating a brachial artery blood pressure cuff above systolic pressure. The figure shows the beginning of cuff inflation (A), when cuff pressure exceeded systolic pressure (B), and after cuff pressure rose above diastolic (C) and systolic (D) blood pressure 445. This demonstrated that variations in skin microcirculation flux could be recorded overtime.
Figure 22. Figure 22. Laser Doppler flowmetry probes, from left to right: (A) a probe containing seven transmitting fibers, a single‐point thermostatic probe enabling local heating, a laser Doppler probe combined with an iontophoresis device that also enables local heating. (B) Laser Doppler Imaging of the right forearm (C) laser speckle contrast imaging of the right hand 97.
Figure 23. Figure 23. Relationship between relative changes (%) in skin temperature recorded using an electrical thermometer and skin blood flow recorded on the big toe by laser Doppler flowmetry (A) and on the dorsum of the foot using laser Doppler imaging (B) during indirect heating following initial cooling. These graphs show a poor agreement in both conditions, and a nonlinear correlation on the big toe 47.
Figure 24. Figure 24. Drugs can be delivered into the skin through microdialysis fibers placed into the derma or at the derma‐hypoderma interface (A), intradermal microinjections (B), or skin iontophoresis (C) 97.
Figure 25. Figure 25. Smoothed circadian rhythm of rectal (Tre, non‐glabrous proximal skin (Tprox, mean of forehead, infraclavicular and thigh temperature) and distal glabrous skin (Tdist from the hand and foot). Data show the same trend for proximal skin temperature and central temperature and an inverse phase for the hand and foot. Temperature is expressed in the Y‐axis as the difference from the mean daily value for each parameter. Note that both are in advanced phase compared to central body temperature (vertical line at 24 h) 275.
Figure 26. Figure 26. Image of the forearm skin of a preterm infant of 24 weeks gestational age obtained through orthogonal polarization spectral imaging. While arterioles and venules can be observed (1, 2, and 3), no pinhead capillary loops can be seen 170.
Figure 27. Figure 27. Forest plots of (A) the mean difference (MD) in macrovascular and (B) the standardized mean difference (SMD) in microvascular endothelium‐dependent reactivity between health groups considered overweight, obese or with cardiometabolic disease, compared to the control healthy group in the network meta‐analyses. CI, confidence interval; IGT, impaired glucose tolerance; MetS, metabolic syndrome; T2D, type 2 diabetes; T2DC, type 2 diabetes with complications. Adapted, with permission, from Loader J, et al., 2019 304.


Figure 1. The anatomy of the skin's microcirculation. This includes the deep horizontal plexus (E) parallel to the skin surface at the derma‐hypoderma interface from which ascending arterioles (C) rise and form a superficial plexus (B) protruding into the derma. Capillary loops (A) are perpendicular to the skin's surface except in specific regions such as nail folds. Arteriovenous anastomoses (D) traverse the superficial plexus and are mostly present in glabrous skin such as the palm of the hands and the sole of the feet. They can have either a glomerular or elongated shape. Other skin features include sweat glands (green) and hair follicles.


Figure 2. Section through the palmer side of a surgically removed finger (supernumerary digit of an 18‐year‐old male) studied by corrosion casting. One can clearly distinguish the papillary layer from which capillary loops arise (i), the subpapillary plexus (ii), the reticular layer (iii), and the hypodermal layer (iv), together with the ascending arterioles (A) and descending venules (B), 400. The regular linear disposition of the capillary loops follows the pattern of the fingerprint lines.


Figure 3. Section through the hypodermal layer of the palmer side of a finger studied by corrosion casting showing an arteriovenous anastomosis located between an arteriole (a) and a venule (v) exhibiting a glomerular‐shaped body 400. Direct connection arteriovenous anastomoses have been described in humans. Endothelial cell nuclei slightly protrude from the vascular lumen as seen on the cast (white arrow).


Figure 4. Forearm blood flow recorded simultaneously by venous occlusion plethysmography in both arms, of the same individual, one of which was pretreated using epinephrine whole forearm iontophoresis (treated arm) and the other used as a control (untreated arm). The difference between them is plotted as absolute forearm skin blood flow. Skin blood flow plotted against muscle blood flow gives a broad spread showing that even when recorded simultaneously in the same territory there is considerable variability between skin and skeletal muscle blood flow 91.


Figure 5. Relationship between capillary pressure in the hand and the distance of the hand below the heart. The subject was initially supine, then sat up and then stood 293. As the extremity of the hand was lowered, the arterial and venous pressures rose linearly with hydrostatic load while capillary pressure rose far less in comparison.


Figure 6. The simultaneous effect of Valsalva's maneuver (respiratory movements recorded on the upper tracing) on intra‐arterial blood pressure (bottom tracing) and sympathetic activity from a median nerve fascicle in skeletal muscles (middle tracing). Valsalva's maneuver is responsible for the initial rise and subsequent drop in systemic blood pressure, and a simultaneous increase in sympathetic activity clearly seen during the drop in blood pressure. Adapted, with permission, from Delius W, et al., 1972 114.


Figure 7. The simultaneous effect of Valsalva's maneuver (respiratory movements recorded on the upper tracing) on intra‐arterial blood pressure (bottom tracing) and sympathetic activity in the skin (middle tracing). In contrast to the skeletal muscles (Figure 6), Valsalva's maneuver had little or no impact on the sympathetic activity of glabrous skin despite an initial rise, followed by a drop in systemic blood pressure 112.


Figure 8. Schematic representation of skin vasodilator pathways. The skin microcirculation is subject to complex neurogenic regulation. First during heat challenges the sympathetic cholinergic system is implicated in the release of acetylcholine, vasoactive intestinal polypeptide (VIP) and pituitary adenylyl cyclase cyclase‐activating peptide (PACAP). Secondly, sensory nerves play a major role in different reflexes through the release of calcitonin gene‐related peptide (CGRP) and substance P, and probably neurokinin A. The endothelium also plays an important role through the release of nitric oxide (NO), prostacyclin (PGI2), and endothelium‐derived hyperpolarizing factors (EDHF) such as the epoxyeicosatrienoic acids (EETs). Pericytes (represented here as the green cell) are frequently found and play a major role in the regulation of vascular tone and tissue regeneration. Different transient receptor potential (TRP) channels are expressed on endothelial cells, smooth muscle cells, and neurons and mediate a wide range of physiological responses. AC, adenylyl cyclase; Ach, acetylcholine; ADM, adrenomedullin; BK, bradykinin receptor B2; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; CLRC/RAMP, calcitonin receptor‐like receptor/receptor activity‐modifying protein; COX, cyclooxygenases; CYP, cytochromes P450; eNOS, endothelial nitric oxide synthase; EP2, prostaglandin EP2 receptor 2; EP4, prostaglandin EP2 receptor 4; GPR68, ovarian cancer G‐protein‐coupled receptor 1; IP, prostacyclin receptor; H1, histamine H1 receptor; HETE, hydroxyeicosatetraenoic acids; IR, insulin receptor; LOX, lipoxygenases; M3, muscarinic acetylcholine receptor 3; MRP4, multidrug resistance‐associated protein 4; NK1, neurokinin 1 receptor; P1A1‐3, A‐type purinergic receptors 1, 2, and 3; P2Y12, P‐type purinergic receptor Y12; PECAM‐1, platelet endothelial cell adhesion molecule 1; PGE2, prostaglandin E2; PGI2, prostacyclin; PIEZO‐1, piezo type mechanosensitive ion channel component 1; PKA, protein kinase A; PKC, protein kinase C; PLA2, phospholipase A2; PPAR, proliferator peroxisome‐activated receptor; RYR, ryanodine receptors; TRP, transient receptor potential channel; VEGFR, vascular endothelial growth factor; VPAC, vasoactive intestinal peptide receptor.


Figure 9. Schematic representation of skin vasoconstrictor pathways. The skin microcirculation is under the influence of neurogenic regulation, represented by the sympathetic adrenergic pathway through the release of norepinephrine (NE) with neuropeptide Y (NPY) and ATP co‐transmission. Cold‐induced norepinephrine‐dependent vasoconstriction is mediated primarily by α2 adrenergic receptors and their mobilization to the cell membrane, depending on the activation of the RhoA‐rho kinase pathway. Endothelin‐1 (ET‐1) induces long‐lasting ETA‐mediated vasoconstriction but also triggers an ET‐A dependent axon reflex in the surrounding area. cAMP, cyclic adenosine monophosphate; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; AT1, angiotensin receptor type 1; ECE, endothelin converting enzyme; eNOS, endothelial nitric oxide synthase; P2X1, P2Y12, P‐type purinergic receptor X1; PLA2, phospholipase A2; PLC, phospholipase C; ROCK, rho‐associated protein kinase; ROS, reactive oxygen species; TRP, transient receptor potential.


Figure 10. Representative experiment (in one subject) in which finger blood flow was monitored using venous occlusion air plethysmography. Blood flow was recorded at thermoneutrality (room temperature 25°C) and during a whole‐body cooling stress (1 h at 20°C room temperature). Phenylephrine, an α1 adrenergic receptor agonist, produced a dose‐dependent decrease in finger blood flow. Clonidine, an α2 adrenergic receptor agonist was more potent (not shown here). Prazosin, an α1 adrenergic receptor antagonist had no effect on basal blood flow but reversed the phenylephrine‐induced reduction in blood flow. During cold exposure, the same dose of prazosin produced only a slight increase in blood flow (mean flow rose from 7.7 to 11.7 mL/min/100 mL) while yohimbine, an α2 adrenergic receptor antagonist increased finger blood flow by the same amplitude seen at thermoneutrality 88. This experiment shows that while adrenergic α1 receptors are present and can respond to the intra‐arterial injection of phenylephrine, the cold‐induced finger vasoconstriction is mediated primarily by alpha‐2 adrenergic receptors.


Figure 11. In this representative experiment, forearm blood flow was recorded using water‐filled venous‐occlusion plethysmographs. The authors assumed that the increased blood flow in the forearm during whole‐body heating was mostly due to skin vasodilatation. Forearm blood flow was continuously measured in neutral thermal conditions (subjects placed in a 34°C bath) and during whole‐body heating (where the bath temperature was raised to reach an oral temperature of 38°C) and subsequent cooling. Cutaneous nerves were anesthetized in one arm (lidocaine injections, black rectangles) and not in the contralateral arm (saline injections, open rectangles). In the control arm, forearm blood flow rose, while nerve blockade blunted the heat‐induced vasodilatation 129. This experiment suggests that during whole‐body heating, microcirculation in the forearm skin is mostly regulated by an active vasodilator mechanism and not by the release of a vasoconstrictor.


Figure 12. Effect on skin blood flow of two concentrations of substance P (top) and CGRP (bottom) infused during 30 min (black bar) through microdialysis fibers placed 660 μm deep into the human skin with and without concomitant 5 μM l‐NAME (a NO synthase inhibitor) infusion. First, it is worth noting that substance P induced an early rise in skin blood flow mediated by NK1 receptors. However, this effect was transient, with skin blood flow decreasing while substance P was still being infused, as a consequence of internalization and subsequent desensitization of NK1 receptors. This early and transient vasodilatation totally contrasts with the effect of CGRP that produced delayed onset and a sustained plateau far beyond the end of the injection. Secondly, the inhibition of nitric oxide production provoked a reduction in baseline blood flux, and an important inhibition of the substance P induced vasodilatation, showing that the substance P effect was partly nitric oxide dependent while its effect on CGRP induced vasodilatation was smaller. Thirdly, substance P induced protein extravasation, which was partly nitric oxide dependent, while CGRP did not (data not shown in this figure) 268.


Figure 13. Prostacyclin was infused at increasing concentrations through four microdialysis fibers in nine healthy young males. One fiber was used as control, one was perfused with LNNA, a nonspecific NO‐synthase inhibitor, one was perfused with the nonspecific KCa channel blocker tetraethylammonium, and one with a combination of both. Both NO synthase and KCa channel blockade decreased the amplitude of prostacyclin vasodilatation, and their addition potentiated their inhibitory effect. This indicates that there is accumulative interaction between the three major endothelial pathways in the human skin, that is, the prostacyclin, nitric oxide, and EDHFs pathways 161.


Figure 14. Individual recordings of hand and forearm blood flow, in ordinate (mL/100 mL/min) using venous occlusion plethysmography before (R for resting) and after increasing concentrations (in μg) of acetylcholine were injected over one min into the brachial artery 119. The data show that the muscarinic receptor agonist acetylcholine was able to induce a concentration‐dependent increase in forearm and hand blood flow, and confirms that muscarinic acetylcholine receptors are present in the microvasculature of the forearm and hand. The apparent reduced efficacy of acetylcholine observed in the hand is due to its rapid degradation by cholinesterases.


Figure 15. Injection of 4 mg of acetylcholine into the brachial artery increased hand skin blood flow during approximately 15 min. In contrast, injection of 0.8 mg atropine had no immediate effect but subsequently prevented acetylcholine vasodilatation 45 min later 168. This shows that muscarinic acetylcholine receptors are present within the hand vascular walls despite the fact that acetylcholine was not released in the vicinity under thermoneutral conditions.


Figure 16. (A) Confocal fluorescence microscopy of human abdominal skin incubated with a NO fluorochrome and then irradiated with ultraviolet A corresponding to natural sunlight exposure at noon on a sunny day. White scale bar: 100 μm. Most fluorescence can be seen within the epidermis when compared with (B) a near contiguous section of hematoxylin and eosin‐stained skin, (C) the addition of l‐NMMA had no effect on ultraviolet A‐induced fluorescence, and (D) the addition of a NO scavenger prevented the any increase in fluorescence 302. This shows that apart from in the vascular endothelium, nitric oxide can also be produced by the epidermis through a non‐NO‐synthase pathway, and induces vasodilatation.


Figure 17. Representative laser Doppler flowmetry tracings of local skin hyperemia expressed as a percentage of maximal skin blood flow during infusion of 50 mM sodium nitroprusside. The classical initial axon reflex dependent peak is followed by a long‐lasting plateau. Most of the plateau vasodilatation was reversed when the NO‐synthase inhibitor l‐NAME was injected intradermally at 40 min (A). When l‐NAME was infused during local heating (B), plateau skin blood flow and to a lesser extent the peak decreased in amplitude 331, showing the major contribution of nitric oxide to the plateau phase.


Figure 18. Intradermal injections of endothelin‐1 induced vasoconstriction on the volar face of human forearm (white circles) and vasodilation in the area surrounding the injection site (A), that was blunted after prolonged pretreatment with capsaicin ointment (B) 503. Therefore, in human skin, endothelin‐1 induces long‐lasting ETA‐receptor mediated vasoconstriction but also triggers an ETA‐receptor dependent axon reflex in the surrounding area.


Figure 19. Palm and forearm cutaneous vascular conductance recorded at baseline and during the last 5 min of a 15 min Valsalva's maneuver during which blood pressure decreased. To avoid the confounding role of sympathetic activity to skin, experiments were performed after ganglionic blockade through intravenous injection of trimethaphan, a short‐acting competitive antagonist of the nicotinic acetylcholine receptors, and compared with control conditions 127. Ganglionic blockade was confirmed because trimethaphan abolished the increase in heart rate during Valsalva's maneuver. Trimetaphan unmasked an increase in skin conductance in both the palms and the forearm showing that these skin vascular beds are capable of dilating in response to pronounced drops in perfusion pressure so as to maintain constant blood flow.


Figure 20. Representative images of nail fold videocapillaroscopy with a magnification of 100×. (A) Normal pattern showing homogenous distribution of capillary loops. (B) Pattern observed in a patient with systemic sclerosis, showing disorganized enlarged/giant capillaries 387.


Figure 21. First in vivo tracing in 1975 of the variation of the skin laser Doppler flow signal over time. Forearm ischemia was performed by inflating a brachial artery blood pressure cuff above systolic pressure. The figure shows the beginning of cuff inflation (A), when cuff pressure exceeded systolic pressure (B), and after cuff pressure rose above diastolic (C) and systolic (D) blood pressure 445. This demonstrated that variations in skin microcirculation flux could be recorded overtime.


Figure 22. Laser Doppler flowmetry probes, from left to right: (A) a probe containing seven transmitting fibers, a single‐point thermostatic probe enabling local heating, a laser Doppler probe combined with an iontophoresis device that also enables local heating. (B) Laser Doppler Imaging of the right forearm (C) laser speckle contrast imaging of the right hand 97.


Figure 23. Relationship between relative changes (%) in skin temperature recorded using an electrical thermometer and skin blood flow recorded on the big toe by laser Doppler flowmetry (A) and on the dorsum of the foot using laser Doppler imaging (B) during indirect heating following initial cooling. These graphs show a poor agreement in both conditions, and a nonlinear correlation on the big toe 47.


Figure 24. Drugs can be delivered into the skin through microdialysis fibers placed into the derma or at the derma‐hypoderma interface (A), intradermal microinjections (B), or skin iontophoresis (C) 97.


Figure 25. Smoothed circadian rhythm of rectal (Tre, non‐glabrous proximal skin (Tprox, mean of forehead, infraclavicular and thigh temperature) and distal glabrous skin (Tdist from the hand and foot). Data show the same trend for proximal skin temperature and central temperature and an inverse phase for the hand and foot. Temperature is expressed in the Y‐axis as the difference from the mean daily value for each parameter. Note that both are in advanced phase compared to central body temperature (vertical line at 24 h) 275.


Figure 26. Image of the forearm skin of a preterm infant of 24 weeks gestational age obtained through orthogonal polarization spectral imaging. While arterioles and venules can be observed (1, 2, and 3), no pinhead capillary loops can be seen 170.


Figure 27. Forest plots of (A) the mean difference (MD) in macrovascular and (B) the standardized mean difference (SMD) in microvascular endothelium‐dependent reactivity between health groups considered overweight, obese or with cardiometabolic disease, compared to the control healthy group in the network meta‐analyses. CI, confidence interval; IGT, impaired glucose tolerance; MetS, metabolic syndrome; T2D, type 2 diabetes; T2DC, type 2 diabetes with complications. Adapted, with permission, from Loader J, et al., 2019 304.
References
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Article Title: Human Skin Microcirculation
 

How to Cite

Jean‐Luc Cracowski, Matthieu Roustit. Human Skin Microcirculation. Compr Physiol 2020, 10: 1105-1154. doi: 10.1002/cphy.c190008