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72 Chapter 7/Molecular Basis of Venous Insuffi ciency
https://t.me/med1917
Naive Leukocytes (NL)
NL + Control Plasma
Patient Leukocytes
NL + Patient Plasma
25
20
15
*
*
*
4
*
*
*
10
NBT Reduction (%)
5
0
FIGURE 7.3 The plasma of (nonsmoking) patients with chronic venous disease contains an infl ammatory mediator.
Fraction of neutrophil activation as detected by nitroblue tetrazolium reduction to zymogen granules (left panel, red
arrow) and by pseudopod projection (right panel, black arrow). Naïve leukocytes (NL) from healthy donors mixed with
patient plasma has signifi cantly higher activated neutrophil counts than either patient blood cells, healthy control cells,
or patient neutrophils mixed with plasma of healthy controls. Adaped from (6). The cause of this activation is an important unresolved question in CVD.
Over the long periods of time required to develop manifestations of venous disease, it is likely that several—if not
all—of these mechanisms may at one time or another stimulate infl ammation in the circulation. The challenge is to
identify prevailing mechanisms in chronic venous disease.
Clearly, the neutrophils of patients with CVD are activated
(see Figure 7.3).
A useful starting point is to look at clinically established
risk factors for venous disease.
99–103
Notable in this respect
are hormonal risk factors associated with pregnancy, especially in the fi rst trimester when less effect on venous blood
fl ow is expected, orthostatic exposure associated with a lack
of blood pressure reduction due to limb movement, and
enhanced body mass index have been cited in many studies.
Such risks may well be associated with cell activation and
in the following I will elaborate. Defi nitive studies have yet
to be carried out.
ELEVATED BLOOD PRESSURE
AND MECHANOTRANSDUCTION
MECHANISMS
One of the oldest treatments for CVD is purely mechanical, a compression bandage wrapped around the diseased
leg. Such compression therapy has an anti-infl ammatory
104
effect
although infl ammatory markers require weeks of
2
Pseudopod Formation (%)
* p< 0.05
treatment
105
before a reduction of infl ammation may be
detectable. Although the exact mechanism is unknown, it is
evident we need to consider mechanical stress.
The evidence that normal and shear stresses exerted by
plasma on cell membranes may control the shape of blood
vessels comes from many different observations. On one
hand, there is some degree of acute control of veins and
venules by passive compression of what are soft viscoelastic
structures.
106
On the other hand, there is also a more chronic
control by mechanical stresses of vascular structure, infl ammation, and thrombosis. Indeed, the shape of even the earliest vascular plexus in the yolk sac may be controlled by fl uid
shear stress.
107
The formation of blood vessels and the
smooth muscle media is directly infl uenced by both normal
stress and by shear stress with synthesis of platelet-derived
growth factors (PDFG-β) by endothelial cells and migration
and differentiation of tissue fi broblasts.
108
Generation of an
abnormal fl uid fl ow fi eld in otherwise healthy blood vessels
within weeks can lead to major vascular remodeling, local
enlargement of vessel lumen to the extreme of mature
aneurysms.
109
The venous hypertension is caused to a large degree by
the lack of venous valves. Therefore outfl ow in proximal
direction during muscle contraction in the legs is impaired
and the veins become exposed to new mechanical stress. The
elevated blood pressure leads to compression of the endothelium and a stretch of the venous wall, and certain locations on the veins become exposed to fl uid shear stress that
Genetic Mechanisms 73
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is disturbed compared with normal veins and intact valves.
This disturbance of the fl uid shear stress is amplifi ed further
as veins change shape and stimulate an effect that profoundly affects the signaling in endothelial cells. There is
now an extensive set of experiments derived in large part
from endothelial cultures that show that many functions of
endothelial cells are controlled by fl uid shear stress (see
References 110–121). Fluid shear stress is a tangential force
produced by moving blood acting on the endothelial surface
and a function of the velocity gradient of blood near the
endothelial surface and the blood viscosity. Even though it
is a small number in the circulation compared to the fl uid
pressure it has a powerful effect on gene expression and the
pro- versus anti-infl ammatory/thrombotic phenotype. Steady
shear stress in a normal physiological range of about 10 dyn/
cm2 is largely anti-infl ammatory, leads to orientation of the
cells in the direction of the fl uid fl ow, with extensive actin
bundle (stress fi ber) formation, a thick endothelium with
relative low infl ammatory activity, extensive attachment to
the underlying extracellular matrix via focal adhesion sites
and interendothelial junctions (cadherins). In contrast, low
fl ow or fl ow disturbances, especially if they involve instances
of reversed fl ow direction with forward and backward shear,
cause a loss of this phenotype, and a cell that is more susceptible to infl ammatory mediators. Stretch of endothelial
cells and smooth muscle cells also has a direct effect on
many aspects of the endothelial biology
122–127
including synthesis and release of many infl ammatory molecules such as
leukotrienes, prostaglandin, bradykinin, free oxygen radicals, and cytokines. Mechanical pressure of the endothelial
cell (but without stretch) produces a response that is distinctly different from that of shear stress and involves growth
factor release.
Leukocytes also respond to fl uid shear stress.
128,129
130
Their
response is different from that of endothelial cells. If activated, they retract their pseudopods; if nonactivated, fl uid
shear stress induces pseudopod formation.
131
Fluid shear
affects the membrane adhesion molecule distribution over
the membrane of leukocytes.
132
The fl uid shear stress
response is infl uenced by the presence and concentration of
infl ammatory mediators in a C-GMP dependent fashion.
133
Blood fl ow cessation, blood stasis that implies lower shear
stress, activates leukocytes as seen by projection of pseudopodia and lamellipodia and membrane attachment as the fi rst
step to transendothelial migration.
These days, blood fl ow in arteries is subject to detailed
fl uid mechanical analysis, which serves to determine the
details of the fl ow fi eld, pressure, and shear stress in arter-
134
ies
and diseases like arterial aneurysms.
135–139
A comparable effort on the venous counterpart is largely missing
today. Thus it is quite plausible that abnormalities in the
fl uid shear stress fi eld in veins, whose diameters are distended, and whose valves have become unable to close properly, may serve as a trigger mechanism for infl ammation.
But the precise role of fl uid stresses on blood cell and endothelial cell activation remains speculative.
PROTEASE ACTIVATION
How can an enhanced body-mass index be associated
with CVD? Certainly there is a possibility that a purely
mechanical mechanism may be involved with obstruction
of blood fl ow in veins of the lower extremities in the presence of enlarged adipose deposits in the abdomen. But there
are other possibilities. Recent work on infl ammation in
shock has brought to light that pancreatic digestive enzymes
in the lumen of the intestine may serve as source for infl ammatory mediators.
the mucosal epithelium in the intestine and enter the wall of
the intestine, self-digestion by pancreatic enzymes is initiated, and in the process fragments of extracellular matrix
proteins and cells are formed that have strong proinfl ammatory properties. These pro-infl ammatory fragments
can enter the circulation via the portal venous circulation,
but also via the intestinal lymphatics, which can diffuse
directly into the peritoneal cavity. Thus the intestine can
readily serve as a source of infl ammatory mediators as long
as there is a compromise to the usually tight permeability
properties of the mucosal barrier. Thus it is interesting to
note that increased intestinal permeability (measured by the
lactulose/mannitol ratio technique) in patients with healed
venous ulcers (class 5, CEAP) but near-normal ambulatory
venous pressure can eliminate high ambulatory venous
pressure as a chronic venous insuffi ciency risk factor.
challenging observation indicates that the source for infl ammation could be gut-derived, and although elevation of
venous pressure, for example after loss of venous valves,
will aggravate the disease process, it may not be the primary
trigger mechanism. Instead a relatively innocent reduction
of the intestinal barrier properties to the powerful digestive
enzymes may be a source for infl ammatory mediators.
Genetic linkage analysis has brought to light that there
are patients with familial risk factors. An imbalance between
collagen I and collagen III has been found in proximal segments of human varicose saphenous veins in addition to
fragmentation of elastin fi brils.
type III is signifi cantly decreased in cultured smooth muscle
cells and dermal fi broblasts derived from patients with varicose veins indicating a defi ciency in collagen type III.
Such type of remodeling of the extracellular matrix has been
proposed to be due to activation of matrix metalloproteinases (MMPs). Expression of MMP-1, MMP-2, MMP-9,
and tissue inhibitor of metalloproteinases-1 has been
140–142
If digestive enzymes escape across
GENETIC MECHANISMS
144
The proportion of collagen
143
This
145
74 Chapter 7/Molecular Basis of Venous Insuffi ciency
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proposed
146,147
with a possible imbalance between these
enzymes and their inhibitors.
CONCLUSION
Among the many steps that make up the infl ammatory
cascade in chronic venous disease, few are as important to
understand as the actual trigger mechanisms. Analysis of
these trigger mechanisms at the molecular lever will provide
us with the tools to prevent and minimize the severity of
the infl ammation and may explain why the infl ammatory
reaction in these patients, even though infl ammation is used
in nature as a process for wound healing, does not come to
a resolution.
Acknowledgment
I would like to thank Dr. John J. Bergan for many years of inspiring
discussions and effective collaborations. Special thanks to my colleagues
Drs. Luigi Pascarella, Shinya Takase, Takeshi Ono, and Alexander Penn,
who carried out the experimental studies summarized in this report. Supported in part by NHLBI grant HL 42063.
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145. Sansilvestri-Morel P, Rupin A, Badier-Commander C, Fabiani JN,
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CHAPTER
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8
Chronic Venous Insuffi ciency: Molecular
Abnormalities and Ulcer Formation
JOSEPH D. RAFFETTO
INTRODUCTION
Chronic venous insuffi ciency (CVI) is a condition that
affects the venous system of the lower extremities rendering
the superfi cial, perforating, and deep veins incompetent.
This results in venous hypertension causing various pathologies including pain, swelling, edema, skin changes, and
ulcerations. The underlying pathology leading to CVI is a
consequence of venous hypertension from valve incompetence causing venous refl ux and/or obstructive disease.1
Varicose veins by defi nition have incompetent valves with
increased venous pressure leading to progressive dilation
and tortuosity. The formation of primary varicose veins is
unknown, but is likely a multifactorial process related to
hereditary, female sex hormones, hydrostatic force, and
hydrodynamic muscular compartments.2 The signifi cance
of protracted venous hypertension from abnormal venous
hemodynamics is the formation of dermal skin changes
referred to lipodermatosclerosis, which leads to dermal and
subcutaneous tissue fi brosis and eventual ulceration.3 This
chapter will review the recent literature supporting the formation of varicose veins, with specifi c interest in the molecular changes in the vein wall of varicosities, and basic
scientifi c studies that have investigated the molecular alterations that are present in advanced CVI disease, namely
dermal tissue fi brosis and venous ulcer formation.
VARICOSE VEINS
Abnormalities with Matrix
Metalloproteinase Metabolism
Varicose veins have characteristically tortuous and dilated
venous walls. A possible explanation for these fi ndings may
be the infl uences of proteolytic enzymes known as matrix
metalloproteinases (MMPs) and their inhibitors known as
tissue inhibitors of metalloproteinases (TIMPs), which lead
to venous wall remodeling and subsequent dilatation and
valvular incompetence. MMPs are highly homologous zincdependent endopeptidases that cleave most of the constituents of the extracellular matrix. To date there are 26 human
MMPs that are classifi ed according to their substrate specifi city and structural similarities. The four major subgroups
of MMPs are gelatinases, interstitial collagenases, stromelysins, and membrane-type matrix metalloproteinases (MTMMPs). MMPs are important enzymes in embryogenesis,
acute tissue healing, remodeling, neoplastic invasion and
metastasis, skin and granulomatous diseases, aging, and
chronic wounds. MMPs are regulated by cytokines, growth
factors, and activation of TIMP that specifi cally degrade and
inactivate MMPs.
In the recent decade there has been a signifi cant interest
in the role of MMPs in the pathophysiology of varicose vein
formation. An early report evaluating the collagen and
elastin content of nonthrombophlebitic varicose veins compared to normal saphenous veins found that there was
increased collagen and a signifi cant decrease in elastin in
both varicose veins and in the vein segment not affected by
valvular incompetence but with varicosities at other sites. In
this study gelatin zymography and elastase activity failed to
demonstrate any differences, indicating the presence of an
imbalance in tissue matrix but not attributable to proteolytic
activity.
segment at the saphenofemoral junction in patients with
varicose veins demonstrated that MMPs activity was
unchanged with that of control, with most of the MMPs
located in the adventitia, and the content of MMP-2 was
decreased but TIMP-1 content was increased.
4
In support of this prior study, evaluation of the vein
5
Neither of
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these two studies supported the role of MMPs in extracellular matrix degradation in the formation of varicose veins;
however, both of these studies examined normal vein tissue
in patients with varicose veins. An additional study investigated the TIMP-1/MMP-2 in varicose veins. A three-fold
ratio increase was found in varicose veins compared to
normal veins and the authors concluded that due to the
favored proteolytic inhibition that extracellular matrix accumulation could account for the pathogenesis observed in
varicose veins.
6
To demonstrate that MMPs were induced by postural
changes in patients with varicose veins, a study sampled
blood from the brachial vein and lower extremity varicose
vein in erect patients following 30 minutes of stasis. The
investigators found that there was an abundant increase of
pro-MMP-9 in the plasma of sampled blood from the varicose vein compared to arm vein. In addition, the proteolytic
activity was associated with increased levels of endothelial
membrane intercellular adhesion molecule-1, vascular cell
adhesion molecule-1, angiotensin converting enzyme, and
L-selectins indicating endothelial cell and polymorphonuclear cell activation and enzymatic granule release in varicose veins during periods of stasis.7 This study provided
evidence that MMPs are important proteolytic enzymes in
patients with CVI that affect the interface of the leukocytes
and endothelium in varicose veins. A number of investigators have specifi cally examined various MMPs in varicose
veins. A current study examining MMP-1, MMP-3, MMP13 in the proximal and distal vein segments in patients with
CVI versus normal control demonstrated that transcriptional
products (mRNA) were not different for MMP-1 or MMP13 in varicose veins versus control nor in proximal versus
distal varicose segments. However, the protein expression
of MMP-1 was elevated in varicose veins compared to controls. In addition, regional variation of MMP-1 and MMP-13
expression were increased signifi cantly in proximal versus
distal varicose segments.8 Other investigators have found
that the morphologic variations of MMPs differ in localization by immunohistochemical technique within the endothelium, media, and adventitia, with elevated amounts of
MMP-1 in smooth muscle and adventitia of varicose veins,
but without any differences in TIMPs. In another study,
MMP-9 was found to have increased immunopositive
staining smooth muscle cells. These fi ndings although not
causative suggest that MMPs may lead to venous wall
degradation and affect the extracellular matrix of the normal
venous wall structure.
Of interest is whether varicose veins with concomitant
thrombophlebitis have variations in MMPs expression compared to varicose veins. In a recent study evaluating MMP1, MMP-2, MMP-3, and MMP-9 activity, it was found that
thrombophlebitic varicose veins had elevated content of
MMPs in the vein wall, with increased gelatinase activity
and MMP-1 activity. Varicose veins had increased activity
of MMP-2. It was concluded that the wall of varicose veins,
especially those affected with thrombophlebitis, have extensive alterations in content and activity of MMPs that may
lead to remodeling and infl uence venous wall mechanical
properties.
9
Alterations in Smooth Muscle Cells,
Dermal Fibroblasts, and Collagen
Several studies have investigated cultured smooth muscle
cells derived from varicose veins to determine if the extracellular matrix modifi cations seen in varicose vein tissue are
related to smooth muscle cells. Smooth muscle cells cultured from varicose veins were found to have decreased
number of cells staining for collagen type III and fi bronectin,
although the transcriptional products of these two proteins
were not dissimilar. The synthesis and deposition of collagen type III but not type I was signifi cantly lower in varicose
veins. When MMPs and TIMPs were analyzed from the
supernatant of confl uent cells no differences were observed.
These fi ndings suggested that the regulation was altered
during posttranscriptional events for both collagen type III
and fi bronectin in smooth muscle cells.10 Further work in
this area demonstrated that varicose greater saphenous vein
has a smaller spiraled collagen distribution specifi cally in
the intima and media.
In an interesting study, investigators evaluated cultured
dermal fi broblasts collagen abnormalities, to determine if
the phenotypic changes observed in venous smooth muscle
cells of patients with varicose veins are also present in their
dermal fi broblasts. The fi ndings from this study demonstrated that the synthesis of collagen type I and the transcript
mRNA product were increased in dermal fi broblasts, but as
in smooth muscle cells, dermal fi broblasts also had decreased
synthesis of collagen type III despite normal transcript.
Among the various MMPs evaluated, pro-MMP-2 was
increased in dermal fi broblasts cultured from patients with
venous disease. The authors concluded that the synthesis of
collagen type III is dysregulated in dermal fi broblasts and is
comparable to the observations of smooth muscle cells
derived from patients with varicose veins, suggesting a systemic alteration in tissue remodeling.
tors demonstrated that with inhibition of MMP with
Marimastat, the production of collagen type III in smooth
muscle cells from varicose veins was partially restored. In
addition MMP-3, which degrades fi bronectin, was elevated
in both transcription product and protein expression. The
authors concluded that the mechanism involved in collagen
type III and fi bronectin degradation in the smooth muscle
cells cultured from varicose veins likely is linked to the
expression of MMP-3.
11
The same investiga-
Varicose Veins 81
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Alterations with Programmed
Cell Death (Apoptosis)
Apoptosis involves cell suicide in response to intrinsic
signals (mitochondrial pathway) or extrinsic stimuli (death
receptor pathway) in order to maintain homeostasis of the
organism. The intrinsic mechanism of apoptosis involves the
mitochondrial pathway. In normal cells the mitochondria
express the bcl-2 protein on their surface that is bound to
Apaf-1 (apoptotic protease activating factor 1). Internal
damage of a cell by oxygen reactive species, drugs, toxins,
and radiation leads to Apaf-1 dissociation with concomitant
Bax protein to enter the mitochondria with resultant cytochrome c egression in the cytosol. Cytochrome c and
Apaf-1 bind to caspase 9 (cysteinyl aspartate-specifi c proteinase, cleave at specifi c aspartic acid residues), forming
an apoptosome that activates other caspases that digest
structural proteins and cleave chromosomal DNA causing
DNA fragmentation. In the extrinsic pathway, the events
that commit a cell to either a path of apoptosis or necrotic
cell death after a specifi c stimulus is dictated in the former
and not the latter by the activation of the central cell
death signal via a specifi c set of surface death receptors that
form a specifi c death domain effector and activate caspase
8. The specifi c inducers of apoptosis include tumor necrosis
factor, neurotransmitters, growth factor withdrawal, IL-2
withdrawal, Fas ligands (expressed on cytotoxic T lymphocytes), whereas oxygen reactive metabolites, viral infection, chemotherapeutic drugs, radiation (UV and gamma),
and toxins can affect both the intrinsic and extrinsic
pathways.
table human diseases including neurodegenerative disorders
(Alzheimer’s, Parkinson’s), autoimmune diseases (lupus,
rheumatoid arthritis), and cancer. In the past fi ve years
investigators have examined the role of apoptosis in varicose
vein formation. In an earlier report the apoptotic index was
48% in control veins and only 15% in varicose veins. Apoptosis was observed only in the adventitia and immunoreactivity was similar for bcl-2 protein but cyclin D1 was
increased signifi cantly in varicose veins, indicating inhibition of apoptosis in varicose veins may be related to changes
in expression of cell cycle events.
observed reduced apoptosis in varicose veins, the same
authors examined the expression of bax protein and of poly
ADP-ribose polymerase (PARP, involved in repair of DNA
damage), which is inhibited by caspases 3 and 6 activation.
In twenty patients with varicose veins, the immunoreactivity
expression of bax and PARP was decreased in the distal
portion of the varicose veins compared to distal control vein
specimens. Both of these studies implicate that reduced
apoptosis may lead to functional abnormalities required in
maintaining the integrity and homeostasis of the vein wall.
12
Alteration in apoptosis is responsible for many intrac-
13
In further exploring the
Other studies support the role of changes in apoptosis regulatory proteins in varicose vein pathophysiology. A recent
study evaluating the distal segment of varicose veins and
controls demonstrated disorganized architecture with
increased collagen fi bers and a decrease in the density and
size of elastic fi bers. In addition, varicose veins exhibited
fewer immunoreactive cells in the media for bax and caspase
9, implicating that the dysregulation of the intrinsic pathway
of apoptosis disrupts normal tissue integrity leading to varicose vein formation.
14
Animal Models of Venous Hypertension
The underlying disturbance leading to varicose vein formation is venous hypertension and valvular incompetence.
There are a few animal models that have investigated the
effect of acute and chronic venous hypertension on molecular changes of the vein wall and valvular function. By creating a femoral artery and vein arterio-venous fi stula an acute
rat model of venous hypertension evaluated valvular changes
and vein wall biochemical characteristics. At three weeks,
three of four rats had demonstrable venous refl ux and
increased venous pressure (94 ± 9 mm Hg, control 11 ±
2 mm Hg) compared to the contralateral control femoral
vein. The pressurized veins were dilated with valve leafl ets,
and length and width were reduced. There was a signifi cant
infl ammatory response represented by leukocytes infi ltrating
the entire vein wall, and upregulation of P-selectin and intercellular adhesion molecules. In this study there were no
differences in MMP-2 or MMP-9 at three weeks, and interestingly the number of apoptotic cells in the vein wall was
increased.15 In a subsequent study, these investigators evaluated both acute and chronic venous hypertension in the
femoral vein of 60 rats by the same methodology. The fi ndings were an increased pressure in the femoral vein
(96±9 mm Hg) with progressive refl ux at 42 days post
arterio-venous fi stula formation. As previously determined
the valves distal to the fi stula demonstrated increased diameter, decreased height, and fi brosis of the valve in the media
and adventitia. Of interest, valve obliteration was observed
and MMP-2 and MMP-9 were elevated signifi cantly after
21 and 42 days of venous hypertension.
studies, a model of venous hypertension is feasible, and
signifi cant endothelial, biochemical, and valve structure
changes of infl ammation and fi brosis are present. However,
only proximal segments of veins were analyzed, and whether
the venous changes are a result from venous hypertension,
venous arterialization, or a combination will require further
work to evaluate if these venous abnormalities are transmitted to distal segments of the axial veins as observed in
human CVI pathology.
16
Based on these
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