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Raynaud's phenomenon and scleroderma dysregulated neuroendothelial control of vascular tone.

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Number 1, January 1995, pp 1 4
0 1995, American College of Rheumatology
Arthritis & Rheumatism
Official Journal of the American College of Rheumatology
Dysregulated Neuroendothelial Control of Vascular Tone
the digits, but can occur in the internal organs. Repeated attacks of RP may contribute to the vascular
disease in SSc by mechanisms of reperfusion endothelial injury, and may contribute to tissue fibrosis, as
illustrated best by the presence of contraction band
necrosis in the myocardium.
Many hypotheses regarding the pathogenesis of
RP have been proposed (8), but to date, the pathophysiology and the mechanisms that promote vasospasm and reduce vasodilatation remain an enigma.
Nonetheless, recent advances in our understanding of
mechanisms of vascular tone control provide an opportunity to revisit the pathogenetic process of RP. It
is now clear that the vascular endothelium and the
platelets are major contributors to the control of
vascular tone (Figure I). Moreover, recent advances
in neurobiology have uncovered a fundamental role for
the peripheral nervous system in this process. Preliminary published observations indicate that neuropeptides are involved in the regulation of pulmonary blood
flow (9) and in kidney perfusion (10). Soluble neuromediators (substance P [SP], neuropeptide Y [NPY],
calcitonin gene-related peptide [CGRP], vasoactive
intestinal peptide [VIP], epinephrine, and norepinephrine) have been shown to interact with the vascular
wall, leading to vascular relaxation or spasm.
A noradrenergic and noncholinergic neurologic
influence on vascular relaxation and constriction has
been demonstrated recently (11). This effect is mediated mainly by the release of neuropeptides that are
present in the sympathetic nervous system (NPY and
norepinephrine), parasympathetic nervous system
In 1862, Maurice Raynaud described coldinduced digital ischemic attacks (l), now referred to as
Raynaud’s phenomenon (RP). Between 3% and 16% of
the general population has RP (2), yet only a small
fraction will develop an associated connective tissue
disease. RP is most prominent in scleroderma (SSc), a
disease renowned for its association with an exaggerated and generalized vasospastic propensity. It is not
clear if the pathophysiology of primary RP and that of
secondary RP are the same. It can be argued that the
pathophysiology of the two forms of RP differs since in
the vast majority of patients, RP does not evolve into
SSc, and most of those in whom it does will have
either positive antinuclear antibody, abnormal nailfold
capillary findings, or both on initial evaluation (3,4).
Microvascular endothelial injury is prominent in SSc
even in the early stages of the disease (5,6). Indeed,
arterial occlusion has been reported particularly in
association with anticentromere antibodies (7). This
degree of vascular disease distinguishes secondary RP
from the primary form.
The vasospastic tendency in SSc can be demonstrated by an early digital arterial closure after cold
stimulation, and by an inadequate vasodilatory response to heat. The phenomenon is not restricted to
Bashar Kahaleh, MD: Medical Cotlege of Ohio, Toledo;
Marco Matucci-Cerinic: University of Cagliari and The Institute of
Internal Medicine, University of Florence, Florence, Italy.
Address reprint requests to Bashar Kahaleh, MD, Professor of Medicine and Chief, Division of Rheumatology, Medical
College of Ohio, P. 0. Box 10008, Toledo, OH 43699-0008.
Submitted for publication March 14, 1994; accepted in
revised form September 8, 1994.
Figure 1. Schematic representation of mediators of vascular tone. SOM = somatostatin; PGE, = prostaglandin E,; PGI, = prostacyclin; HIS = histamine; VIP = vasoactive intestinal peptide; NO = nitric oxide;
ACH = acetylcholine; SP = substance P; CGRP = calcitonin gene-related peptide; SHT = serotonin; NEP
= neutral endopeptidase; NY = neuropeptide Y; NEN = norepinephrine; TXA, = thromboxane A,; EN =
epinephrine; ET = endothelin.
(VIP and acetylcholine), and sensory nervous system
(SP and CGRP). Some of these mediators are identified as vasoconstrictors (NPY) and some as vasodilators (CGRP, SP, VIP) (Figure 1). Their action may be
endothelium dependent (SP) or they may act directly
on the smooth muscle cells (CGRP, NPY, VIP),
The control of neuropeptide secretion is still
poorly understood, yet it is interesting to note that
thermal stimulation may induce their secretion (12).
Sensory neuropeptides are found in abundance in
human skin (13), where they are involved not only in
the transmission of thermal and noxious stimuli, but
also in the control of skin blood flow (14).For example, injection of SP into the skin produces an intense
vasodilatory response (15). This phenomenon is tied
entirely to the integrity of the peripheral nervous
system, since it can be suppressed by previous longterm treatment with capsaicin, which depletes the
sensory neuropeptide reservoir (16). Furthermore, the
peripheral sensory nerves produce not only vasodila-
tion, but also a vasopermeability effect (16). The
inflammation induced by physical, thermal, or chemical stimuli or injury is entirely abolished by conditions
associated with degeneration of the sensory nerves,
and thus is dependent on the integrity of the neurons.
Moreover, the chronic exposure of neurofibers to
capsaicin leads to a state of unresponsiveness to
chemical stimuli, with subsequent failure to develop
neurogenic inflammation (16).
The finding that the sensory afferent system
may also have an “efferent” function has been a
fundamental step in the appreciation of the mechanisms involved in neurogenic inflammation (17). Furthermore, the peripheral endings of the primary afferent sensory neurons not only transmit nociceptive
stimuli, but also induce vasodilation, increase venular
permeability, modify the activity of the immune system, and have cellular mitogenic effects (proliferation
of vascular smooth muscle cells, fibroblasts, and
lymphocytes), in addition to their role in vascular tone
control (contraction or relaxation of vascular smooth
muscle) (18).
It is now clear that the control of vascular tone
represents an interplay between three central groups
of vascular mediators. The interaction of neuropeptides, products of the vascular endothelium (endothelin [a vasoconstrictor] and endothelial-dependent
relaxation factor [EDRF] and prostacyclin [vasodilators]), and platelet release products (serotonin, platelet factor 4, /3-thromboglobulin) results in the delicate
control of vascular tone (19-22) (Figure 1). Investigations indicate the presence of a heightened vasospastic
environment in RP, driven partly by products of the
vascular wall. Increased synthesis and release of the
vasoconstrictor peptide endothelin has been reported
(23) in association with failure of EDRF release upon
cold stimulation (24). Furthermore, platelet activation
and release of platelet products in SSc is now well
established (25). Still, the role of neuropeptides in this
process is not known. Neuropeptide involvement in
the vasospastic attack of RP may be of critical importance in the understanding of the mechanism that
governs this phenomenon, in view of the central role
of neuropeptides in the control of vascular tone. The
current hypothesis suggests the presence of a dysregulation of the neural control of vascular tone in RP,
manifested by deficiency of vasodilatory neuropeptides, possibly due to sensory system damage.
Widespread changes in the neural network in
SSc, characterized by a uniform and dynamic neuronal
degeneration in the affected and nonaffected skin, are
reported (26,27). A neurologic dysfunction, particularly sensory in nature, has been described in SSc (28).
Some studies have shown an autonomic dysfunction
(29,30); still, few investigations have focused on the
study of the peripheral nervous sensory system in this
disease. There is only one report, by Terenghi et a1
(3 l), that describes a significant general decrease of
CGRP and VIP in the epidermis and around capillaries
in dermal papillae of patients with SSc. Moreover, a
marked decrease of protein gene product 9.5, a marker
for neuronal elements in epidermal and subepidermal
layers of digital skin, was also noted (31).
Furthermore, a preliminary investigation of
plasma levels of SP and CGRP (products of the sensory nervous system) in 23 patients with limited SSc,
divided into two groups (early and late/atrophic stages
of the disease) (18), showed that SP levels in the group
as a whole and in those whose disease was in the early
phase were not different from control values. However, in patients whose disease was in the late atrophic
phase, SP levels were significantly reduced when
compared with the early-disease group as well as with
the control group. A reduction in CGRP levels was
seen in the group as a whole and in those with early
disease, and was marked in those whose disease was
in the atrophic phase.
These results, together with those of Terenghi
et a1 (31), suggest a progressive depletion of the
peripheral nervous system fibers. This process may
lead to impairment in the neuronal input in vascular
tone control, leaving the vascular wall as the sole
controller of blood flow. The current hypothesis on the
pathogenesis of RP suggests the presence of a state of
sensory nervous system failure in SSc, leading to
unopposed endothelial and platelet control of vascular
tone. Endothelial injury and platelet activation in SSc
propagate a shift in vascular wall function from a
vasodilatory function to a pro-vasospastic function
unopposed by a vasodilatory sensory input; thus,
enhanced vasospasm is generated. Increased endothelin synthesis and release and reduction in EDRF
synthesis are regularly demonstrated in arteriosclerosis, essential hypertension, and diabetes, yet in SSc,
the unique site of vascular pathology and the presence
of a neural defect may contribute to the development
of RP.
Injury to the vascular endothelium and subsequent platelet activation are fundamental in disease
pathogenesis. Yet structural and functional impairment of the perivascular neurofibers may be essential
to the genesis of vasospasm in scleroderma. Dysregulation of vascular tone lends support to the local fault
hypothesis in the pathogenesis of RP (32). Better
understanding of the mechanisms of this dysregulation
should lead to the design of new vasodilatory treatment strategies which could be useful in the control of
the vasospasm in the peripheral extremities as well as
in internal organs. The recently reported favorable
experience using CGRP in the treatment of severe RP
(33) supports the promise of this approach.
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phenomena, raynaud, vascular, dysregulated, tone, scleroderma, neuroendothelial, control
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