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100 A. Patel et al.
causes an increase in blood flow by release of acetylcholine in the endothelial layer.
This activates muscarinic receptors to release nitric oxide causing smooth muscle
relaxation and vasodilation.
Arterial and Venous Components of Blood Pressure Regulation
Innervation of the mesenteric vasculature is essential for vasoconstriction and
dilation. These functions are required for regulation of blood pressure as well as
potentially liberating large quantities of blood for use elsewhere i.e. fight or flight
instincts. The splanchnic circulation is inner vated by both the sympathetic division
of the autonomic nervous system and by spinal sensory nerves.
The differences in regulation of vascular resistance and capacitance cannot be
accounted for solely based on the sympathetic innervation. Primary sensory neurons
also provide substantial innervation to the vasculature as well as to the sympathetic
neurons that innervate the blood vessels. Furthermore, the vascular endothelium
provides a modulatory infl uence on neurogenic contractions of artery and vein. The
interaction of sensory and sympathetic innervation of arteries and veins with each
other and with other modulatory influences such as endothelium are an important
component of understand blood pressure regulation.
Neuronal Control of Mesenteric Arteries and Veins
When juxtaposing mesenteric artery and vein neuroeffector transmission, two major
differences are apparent. Relatively rapid excitatory junction potentials can be
recorded from arteries, but not from veins. This excitatory junction potential is
mediated by ATP released from sympathetic nerves acting on P2X recept ors on
vascular smooth muscle cells. In addition, repetitive nerve stimulation produces a
slow arterial and venous depolarization. However, the effect of this depolarization
on the resulting contraction of the vasculature is proportionally greater for a given
frequency of nerve stimulation in the veins than in arteries. In the mesenteric
arteries, repetitive nerve stimulation also produces a long-lasting inhibitory junction
potential that mediates vasodilation. This response is mediated by spinal sensory
nerves. This inhibitory junction potential and its associated vasodilatation can be
evoked in the mesenteric arterial supply of the colon and results in colonic distension (Fig. 12.2).
12 Neurophysiologic Function of the Mesentery 101
Fig. 12.2 The above schematic demonstrates how mesenteric arteries and veins are provided
sensory innervation. The artery and vein react differently, as indicated by the stimulus curves, to
single and repetitive stimuli. Cellular responses to nerve stimulation and distension of the colon are
indicated inside the boxes. Reused from Kreulen, DL. Properties of the Venous and Arterial
Innervation in the Mesentery. Journal of Smooth Muscle Research 2003;39(6), 269–279.
Copyright © Japanese Society of Smooth Muscle Research
Anatomic Organization of Sympathetic Innervation of the Large Intestine
The mesenteric arteries that supply the large intestine are innervated by sympathetic
neurons in the inferior mesenteric ganglion. Using retrograde tracers placed in the
lumen of mesenteric arteries and veins that supply the large intestine, it has been
shown that neurons in the inferior mesenteric ganglion that innervate arteries are
different from those that innervate veins. Furthermore, the arterial neurons are
localized in the core of the inferior mesenteric ganglion whereas the venous neurons
are localized near the boarders.
102 A. Patel et al.
Activation of Vascular Innervation by Peripheral Reflexes
Peripheral reflexes are mediated solely outside of the central nervous system and
involve pathways that travel through various ganglia. Distension of the intestine
activates primary afferent neurons that innervate the mesenteric blood vessels as
well as sympathetic ganglia. Thus, intestinal distension can evoke an inhibitory
junction potential in mesenteric blood vessels. This inhibitory junction potential is
an important promoter of vasodilation. Sensory nerves that are activated by
intestinal distension include primary sensory nerves whose cell bodies are within
the dorsal root ganglia and intestinal afferents wi th the cell bodies in the myenteric
plexus of the intestine. Both types of afferents depolarize neurons in prevertebral
sympathetic ganglia and thus may evoke vasoconstrictor responses via this pathway. Nerve depolarization within the prevertebral ganglia function to counteract the
direct vasodilatory response evoked by primary sensory nerve activation.
Innervation of the Lymphatic Vessels
While there is significant data available for innervation of arteries and veins of the
mesentery, information regarding neurologic interactions with lymphatic vessels is
much more limited. It is generally believed that the walls of mesenteric lymphatic
vessels have decreased innervation compared to blood vessels. Most nerve fibers
are confined to the adventitia of lymphatic vessels while nerve fibers are typically in
the tunica media of arteries and veins. In human anatomy, cholinergic nerve fibers,
though few in quantity, have been described and are localized in the wall of large
mesenteric lymphatic vessels. Although the exact mechanism respon sible for lymph
flow is unclear, two predominating hypotheses have b een described. The first is that
lymphatic flow is a passive phenomenon without the role of actively contracting
lymphatic vessels. Propulsion of lymphatic fluid is mediated by extrinsic tissues
compressing lymphatic vessels. This is supported by the relatively small quantity of
cholinergic nerve fibers found in lymphatic vessels. The second hypothesis is that
active contraction of the smooth muscle cells surrounding the wall of the lymphatic
vessel that is controlled by sympathetic stimulation and cholinergic action on
mesenteric arteries. Release hormonal peptides such as substance P are hypothesized to cause lymphatic vessel wall contraction. This phenomenon occurs following an increase in intraluminal pressure or chemical stimuli.
12 Neurophysiologic Function of the Mesentery 103
The Mesenteric Nervous System and Inflammation
New research is emerging that highlights the function of the mesenteric nervous
system in the control of inflammation. The vagus nerve has an important role in
maintaining homeostasis between pro and anti-inflammatory mechanisms in the
mesentery and the bowel. During times of stress and inflammation, vagal afferent
neurons are activated in response to cytokine and endotoxin release. Inflammation
enhances neuroplast icity and signaling sensitivity via upregulation of dendritic
receptors, modulating sodium ion channel density and function, and inducing
reactive gliosis of satellite glial cells. The resulting central effects of these processes
include fever, nausea, vomiting and weight loss. Peripheral effects occur after
sympathetic neuronal-mediated release of catecholamines and glucocorticoids. The
vagus nerve also plays an anti-inflammatory role. It has been established that the
release of acetylcholine from vagal efferent nerves acts to inhibit pro-inflammatory
cytokines such as tumor necrosis factor (TNF). There is also evidence of communication between the autonomic nervous system and T cells that results in the
induction of a cholinergic response. Activated sympathetic neurons in the mesenteric ganglia promote the release of noradrenalin (norepinephrine) and substance P
(SP). Enteric neurons containing SP are located in myenteric and submucosal
plexuses throughout the gastrointestinal tract. The effects of SP begin with ligation
of G-protein-coupled NK-1R. NK-1R induces proinflammatory signaling characterized by the production of a considerable quantity of proinflammatory molecules.
Direct neuromodulatio n of immune response is also demonstrated by acetylcholine.
The acetylcholine receptor alpha 7 subunit (a7nAChR) is the component of
acetylcholine that is responsible for inhibiting macrophage production of
TNF-alpha production. Transmembrane proteins (TLRs) are present in both gastrointestinal tissue and nervous tissue. TLRs play a role in stimulating the production of proinflammatory cytokines. Gelatinase, a protein secreted by E. faecalis,
is associated with increased colonic epithelial permeability. Pro teinase-activated
receptors (PARs) are expressed throughout the gastrointestinal tract. PAR2 has
been is involved in neuronally-induced colonic inflammation. These factors and
cholinergic activity combine to regulate proinflammatory cytokines that are
released from macrophages and other immunocytes (see Fig. 12.3).
104 A. Patel et al.
Fig. 12.3 Interaction between the enteric neuron system (ENS) and mucosal immune cells. Upon
vagus nerve stimulation, sympathetic innervation produces neurotransmitters that can modulate
immune cells and the inflammatory response. The intestinal microbiota also participates in the
inflammatory response, resulting in fine-tuning of the interaction between the ENS and mucosal
immune cells. Ach = acetylcholine, SP = substance P, a7nAChR = acetylcholine receptor alpha 7
subunit, TLR=Toll-like receptors. Reused from Bernardazzi C, BPêgo B, de Souza HSP. Neuroimmunomodulation in the Gut: Focus on Inflammatory Bowel Disease. Mediators of
Inflammation 2016; Article ID 1363818 https://doi.org/10.1155/2016/1363818. Copyright ©
2016 Claudio Bernardazzi et al. This is an open access article distributed under the Creative
Commons Attribution License, which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited
12 Neurophysiologic Function of the Mesentery 105
Suggested Reading
1. Standring S, Gray H. Grays anatomy: the anatomical basis of clinical practice. Philadelphia:
Elsevier; 2016.
2. Li Y, Zhu W, Zuo L, Shen B. The role of the mesentery in Crohn’s disease: the contributions
of nerves, vessels, lymphatics, and fat to the pathogenesis and disease course. Inflamm Bowel
Dis. 2016;22(6):1483–95. https://doi.org/10.1097/MIB.0000000000000791.
3. Sahin A, Artas H, Eroglu Y, Tunc N, Oguz G, Demirel U, Bahcecioglu IH, et al. A neglected
issue in ulcerative colitis: mesenteric lymph nodes. J Clin Med. 2018;7(6):142. https://doi.org/
10.3390/jcm7060142.
4. Kiernan MG, Calvin Coffey J, McDermott K, Cotter PD, Cabrera-Rubio R, Kiely PA,
Dunne CP. The human mesenteric lymph node microbiome differentiates between Crohn’s
disease and ulcerative colitis. J Crohn’s Colitis. 2019;13(1):58–66. https://doi.org/10.1093/
ecco-jcc/jjy136.
5. Mao R, Kurada S, Gordon IO, Baker ME, Gandhi N, McDonald C, Calvin Coffey J, Rieder F.
The mesenteric fat and intestinal muscle interface: creeping fat influencing stricture formation
in Crohn’s disease. Inflamm Bowel Dis. 2019;25(3):421–426. https://doi.org/10.1093/ibd/
izy331.
6. Drake RL, Vogl W, Mitchell AWM, Gray H. Gray’s anatomy for students. Philadelphia:
Elsevier/Churchill Livingstone; 2005.
7. Rivera ED, Calvin Coffey J, Walsh D, Ehrenpreis ED. The mesentery, systemic inflammation,
and Crohn’s disease. Inflamm Bowel Dis. 2019;25(2):226–234. https://doi.org/10.1093/ibd/
izy201.
8. Harper D, Chandler B. Splanchnic circulation. BJA Educ. 2016;16(2):66–71. https://doi.org/
10.1093/bjaceaccp/mkv017.
9. Kreulen DL. Properties of the venous and arterial innervation in the mesentery. J Smooth
Muscle Res. 2003;39(6):269–79. https://doi.org/10.1540/jsmr.39.269.
10. Browning KN, Verheijden S, Boeckxstaens GE. The vagus nerve in appetite regulation, mood
and intestinal inflammation. Gastroenterology. 2017;152(4):730–44.
11. Bernardazzi C, Pêgo B, de Souza HSP. Neuroimmunomodulation in the gut: focus on
inflammatory bowel disease. Med Inflamm. 2016;2016(3):1– 14. Article ID 1363818. https://
doi.org/10.1155/2016/1363818.
12. Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergic anti-inflammatory
pathway: a missing link in neuroimmunomodulation. Mol Med. 2003;9(5–8):125–34.
13. Nguyen C, Coelho A-M, Grady E, et al. Colitis induced by proteinase-activated receptor-2
agonists is mediated by a neurogenic mechanism. Can J Physiol Pharmacol. 2003;81(9):920–7.
Physiology of the Mesenteric Circulation
Saad Hashmi, Ahmed Khattab, and Eli D. Ehrenpreis
Introduction
Although the terms “mesenteric circulation” and “splanchnic circulation” are frequently used interchangeably, they are not synonymous. The “mesenteric circulation” stringently describes the blood supply to the small inte stine, ascending colon
and the proximal two-thirds of the transverse colon. The “splanchnic circulation” is
a broader term that refers to the vasculature of the gastrointestinal tract and its
associated organs (liver, pancreas and spleen).
The superi or mesenteric artery is the major supplying vessel to the mesenteric
circulation. It receives approximately 12% of the cardiac output. Under normal
conditions, the flow rate of the superior mesenteric artery is 700 mL min. However,
this flow rate can vary from 500 to 1300–1400 mL min (Figs. 13.1 and 13.2).
Several factors interplay to achieve such a wide range of blood flow. Such
mechanisms are broadly categorized as either intrinsic or extrinsic and are described
in more detail below. To better understand those mechanisms, it is necessary to
review the structure and function of the mesenteric microcirculation as well as the
physiologic properties of fluid dynamics.
13
S. Hashmi
Department of Internal Medicine, Advocate Lutheran General Hospital, Skokie, IL, USA
A. Khattab
Department of Internal Medicine, Division of Gastroenterology, Advocate Lutheran General
Hospital, 1775 Dempster St, 6 South, Park Ridge, IL 60068, USA
E. D. Ehrenpreis (&)
Department of Medicine, Advocate Lutheran General Hospital, 1775 Dempster St, 6 South,
Park Ridge, IL 60068, USA
e-mail: e2bioconsultants@gmail.com
© Springer Nature Switzerland AG 2021
E. D. Ehrenpreis et al. (eds.), The Mesenteric Organ in Health and Disease,
https://doi.org/10.1007/978-3-030-71963-0_13
107
108 S. Hashmi et al.
Mammary
artery
700 ml/min
Portal vein
Celiac artery
800 1100 ml/min
0 ml/min
10
Sup. mesenteric artery
500 1400 ml/min
Aorta
Inf. mesenteric artery
400 ml/min
Radix mesenterica
Pancreas
Duodenum
Internal iliac artery
Superior
mesent
vein
eric
Inferior
mesenteric
vein
Fig. 13.1 Schematic representation of blood supply of celiac, superior mesenteric and inferior
mesenteric arteries with corresponding average flow rates
Review of Mesenteric Microcirculation and Fluid Dynamics
Mesenteric Microcirculation
There are three components to the mesenteric microcirculation: microscopic arteries
and arterioles (resistance vessels), capillaries (exchange vessels) and microscopic
veins (capacitance vessels) (Figs. 13.3 and 13.4). The mesenteric mucosal circulation has an in-series relationship with the circulation of the submucosal layer of
the intestine and an in-parallel relationship with the circulation of the muscular
layer. This allows for fluctuations in blood flow to the mesentery only, without
affecting total intestinal blood flow. The microscopic arteries and arterioles are also
known as resistance vessels because they have the capability to constrict or dilate as
a response to hormonal or neuronal influences. Changes in vascular diameter
produce increases and decreases in local blood pressure, which in turn influence
local blood flow. Sympathetic neuronal output in the form of catecholamines and
13 Physiology of the Mesenteric Circulation 109
Fig. 13.2 Another schematic
representation of blood supply
of celiac, superior mesenteric
and inferior mesenteric
arteries with corresponding
average flow rates
to the heart
Liver
Hepatic artery
1300 ml/min 700 ml/min
Portal vein
Stomach
Spleen
Pancreas
Small
intestine
Colon
from the heart
500 ml/min
Celiac artery
700 ml/min
Superior
Mesenteric artery
Interior
Mesenteric artery
400 ml/min
Aorta
hormones such as vasopressin have the largest influence on the mesenteric circulation by producing vasoconstriction of these resistance vessels. It is important to
note that under pathologic conditions, such as long-standing hypertension, resistance vessels can undergo hypertrophic remodeling resulting in a decrease in the
diameter of the vessels leading to decreased blood flow.
The capillaries are the site where oxygen, nutrients and fluids move into cells
from the arterial circulation and metabolic byproducts, CO
and heat are transported
2
out of cells into the venous circulation. Thus, these capillaries are know n as
exchange vessels. Blood flow to the exchange vessels is regulated by precapillary
sphincters. When the precapillary sphincters contract, blood flow to the exchange
vessels is shut down , resulting in a reduction of the exchange process. Following
relaxation of the precapillary sphincters, blood flow to the capillaries resumes and
there is an increase in exchange of arterial and venous systems. Blood drained from
the capillaries ultimately returns via the venous system. The venous system is
characterized by thin-walled vessels having smooth muscle layers that respond to
external stimuli. Venous contraction accentuates blood return to the heart. Nearly
80% of the total blood flow of the mesenteric microcirculation is contained within
110 S. Hashmi et al.
Capillary bed
Capillary
Arteriole
Precapillary
sphincter
Metarteriole (serves
as vascular shunt
when precapillary
sphincters are
closed)
Arteriovenous
anastomosis
Venule
Thoroughfare
channel
Fig. 13.3 The mesenteric microcirculation is comprised of three major components: microscopic
arteries and arterioles, capillaries and microscopic veins. Blood flow to the capillaries is regulated
by the precapillary sphincters
the microscopic veins. Because storage of blood occurs within the venous system,
vessels within this system are known as capacitance vessels.
Fluid Dynamics
Poiseuille’s equation states that flow within a vessel (in this case blood flow) is
equal to the change in pressure divided by resistance and is written as such:
Blood flow ¼ DP/Resistance
Resistance is affected by three main variables: Fluid viscosity, vessel length and
vessel radius. The relationship of these variables is demonstrated by the following
equation:
Resistance ¼ 8gL=pr
4
In this equation, 8 and p are constants, η = fluid (blood) viscosity, L = length of
the vessel, and r = radius of the vessel (Fig. 13.5).
Practically speaking, since viscosity and blood vessel length do not readily
change, the main factor determining resistance to blood flow is the diameter of the
vessel. Therefore, despite the variety of factors interplaying to alter blood flow, the