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contractile to a secretory phenotype is currently unknown. It has been suggested that SMC
dedifferentiation may be related to alterations in apoptosis mediators such as bax and PARP
(Poly ADP-ribose polymerase) and/orincreased phosphorylationof differentiationmediators
such as the retinoblastoma protein (13,18,19). The molecular regulation of vein wall
degeneration is currently ill-defined and requires further research.
Vein wall remodeling has been consistently observed in histologic varicose vein
specimens (12,14–17,20). Gandhi et al. quantitatively demonstrated an increase in
collagen content and a decrease in elastin content compared to normal GSVs (20). The net
increase in the collagen/elastin ratio suggested an imbalance in connective tissue
matrix regulation. As a result, several investigators have observed alterations in matrix
metalloproteinase and fibrinolytic activity in varicose veins. TIMP-1 and MMP-1 protein
levels are increased at the saphenofemoral junction compared to normal controls whereas
MMP-2 levels are decreased (21). No overall differences in MMP-9 protein or activity
levels have been identified. However, the number of cells expressing MMP-9 by
immunohistochemistry has been reported to be elevated in varicose veins compared to
normal veins (22,23). There are conflicting reports regarding the role of plasmin activators
and their inhibitors. Shireman et al. reported that uPA (urokinase plasminogen activator)
levels are increased three to five times compared to normal controls in the media of vein
specimens cultured in an organ bath system (24). No differences were noted in tPA (Tissue
Plasminogen Activator) or PAI-1 (Plamin Activator Inhibitor-1) levels. However, other
investigations have reported a decrease in uPA and tPA activity by enzyme zymography in
varicose veins (22,25). These data suggest that the plasminogen activators may play a role
in matrix metalloproteinase activation leading to vein wall fibrosis and varix formation.
Abnormal Vein Wall Function in Varicose Veins
Varicose veins clearly demonstrate abnormal contractile properties. The contractile responses
of varicose and normal GSV rings to noradrenaline, potassium chloride, endothelin, calcium
ionophore A23187,angiotensin IIand nitric oxidehavebeen evaluatedby several investigators
(26,27). These studies have demonstrated decreased contractility of varicose veins when
Figure 2 Electron micrograph of varicosed greater saphenous vein (magnification 4240!).
Smooth muscle cells exhibit prominent vacuoles (arrows) and an elliptical appearance consistent
with a secretory phenotype. Smooth muscle cells are separated by diffusely deposited collagen
bundles, which impart a disorganized architectural appearance to the vein wall.
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stimulated by noradrenaline, endothelin and potassium chloride. Similarly, endothelium
dependent and independent relaxations after A23187 or nitric oxide administration were
diminished compared to normal GSVs, respectively. The mechanisms responsible for
decreased varicose vein contractility appear to be receptor mediated (27,28). Utilizing
Sarafotoxin S6c (selective pharmacologic inhibitor of endothelin B) and competitive inhibition
receptor assays with
131
observed in varicose veins compared to normal GSVs (28). Feedback inhibition of receptor
production secondaryto increased endothelin-1 is postulated tomediate the decreased receptor
content in varicose vein walls. Other possible mechanisms for decreased contractility appear
related to cAMP levels and the ratio of prostacyclin to thromobxane-A2 (29). Cyclic-AMP is
increased in varicose vein specimens compared to normal GSVs. In addition, the ratio of
prostacyclin to throboxane-A2 is increased although no difference in absolute protein levels
between normal veins and varicosities were observed. Whether venodilation of varicosities is
caused by diminished endothelin receptor levels and responsiveness to cAMP or a secondary
effect of varix formation is not known. However, it is clear that with the development of vein
wall fibrosis, varicose veins demonstrate decreased contractile properties that probably
exacerbate the development of ambulatory venous hypertension.
HISTORICAL THEORIES OF CVI
In the twentieth century numerous theories have been postulated regarding the etiology and
pathophysiology of CVI and the cause of venous ulceration. The venous stasis, arteriovenous
fistula and diffusion block theories have been disproven over time and are discussed here for
historical interest only. The etiology for dermal skin pathology is primarily a chronic
inflammatory process and the events regulating these events are discussed below.
Venous Stasis Theory
In 1917, John Homans published a manuscript entitled The Etiology and Treatment of
Varicose Ulcer of the Leg in Surgery, Gynecology and Obstetrics (30). This work was a
clinical treatise on the diagnosis and management of patients with CVI. Homans coined
the term post-phlebitic syndrome and speculated that venous ulceration was secondary to
venous stasis (30). This hypothesis resulted in a generation of investigators trying to seek a
causal relationship between hypoxia, stagnant blood flow and the development of CVI.
The first investigator to address the question of hypoxia and CVI scientifically was
Alfred Blalock (31). He obtained venous samples from the femoral, greater saphenous and
varicose veins in 10 patients with CVI isolated to one limb and compared their oxygen
content to samples taken from corresponding veins in the opposite limb. Seven of the
patients had active ulcers at the time. All samples were collected in the recumbent and
standing positions. He reported that in patients with unilateral CVI the oxygen content was
higher in the femoral vein of the affected limb. He speculated that this observation may be
reflective of increased venous flow rather than stagnation.
Arteriovenous Fistula Theory
The concept of increased venous flow in the dermal venous plexus was expanded upon by
Pratt who reported that increased venous flow in patients with CVI could be clinically
observed (32). He attributed the development of venous ulceration to the presence of
arteriovenous connections and coined the term “arterial varices.” He reported that in a
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series of 272 patients with varicose veins who underwent vein ligation, 24% had
arteriovenous connections. Of the 61 patients who developed recurrences, 50% occurred
in patients with arteriovenous communications identified clinically by the presence of
arterial pulsations in venous conduits. Pratt hypothesized that increased venous flow
shunted nutrient and oxygen rich blood away from the dermal plexus leading to areas of
ischemia and hypoxia and resulting in venous ulceration. Pratt’s clinical observations
however, have never been confirmed with objective scientific evidence. Experiments with
radioactively labeled microspheres have never demonstrated shunting and have therefore
cast serious doubts on the validity of this theory.
Diffusion Block Theory
Hypoxia and alterations in nutrient blood flow were again proposed as the underlying
etiology of CVI in 1982 by Burnand et al. (33). These authors performed histologically
analyzed skin biopsies from 109 limbs of patients with CVI and 30 limbs from patients
without CVI and measured venous pressure at rest and after heel raises. The authors
reported that venous hypertension was associated with increased numbers of capillaries
in the dermis of patients with CVI. Similarly, in a canine hind limb model, the same
authors were able to induce enlargement in the number of capillaries with experimentally
induced hypertension (34). This important investigation was one of the first studies to
demonstrate a direct effect of venous hypertension on the venous microcirculation. In a
later study, Browse and Burnand noted that the enlarged capillaries observed on
histologic examination exhibited pericapillary fibrin deposition and coined the term
“fibrin cuff” (35). They speculated that venous hypertension led to widening of
endothelial gap junctions with subsequent extravasation of fibrinogen leading to the
development of fibrin cuffs. These authors theorized that the cuffs acted as a barrier to
oxygen diffusion and nutrient blood flow, resulting in epidermal cell death. Although
pericapillary cuffs do exist, it has never been demonstrated that they act as a barrier to
nutrient flow or oxygen diffusion.
Leukocyte Activation
Dissatisfaction with the fibrin cuff theory and subsequent observations of decreased
circulating leukocytes in blood samples obtained from the greater saphenous veins in
patients with CVI led Coleridge Smith and colleagues to propose the leukocyte trapping
theory (36). This theory proposes that circulating neutrophils are trapped in the venous
microcirculation secondary to venous hypertension. The subsequent sluggish capillary
blood flow leads to hypoxia and neutrophil activation. Neutrophil activation leads to
degranulation of toxic metabolites with subsequent endothelial cell damage. The ensuing
heterogenous capillary perfusion causes alterations in skin blood flow and eventual skin
damage. The problem with the leukocyte trapping theory is that neutrophils have never
been directly observed to obstruct capillary flow therefore casting doubt on its validity.
However, there is significant evidence that leukocyte activation plays a major role in the
pathophysiology of CVI.
Role of Leukocyte Activation and Function
In 1988, Thomas et al. reported that 24% fewer white cells left the venous circulation after
a period of recumbency and that packed red blood cell volume increased in patients with
CVI compared to normal patients (37). They also noted that the relative number of white
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cells, were significantly decreased compared to control and primary varicose vein patients
(28% vs. 5%, p!0.01). The authors concluded that the decrease in white cell number
was due to leukocyte trapping in the venous microcirculation secondary to venous hyper-
tension. They further speculated that trapped leukocytes may become activated resulting
in release of toxic metabolites causing damage to the microcirculation and overlying skin.
These important observations were the first to implicate abnormal leukocyte activity in the
pathophysiology of CVI.
The importance of leukocytes in the development of dermal skin alterations was
emphasized by Scott et al. (38). These authors obtained punch biopsies from patients
with primary varicose veins, lipodermatosclerosis, and patients with lipodermatosclerosis
and healed ulcers and reported the median number of white blood cells (WBCs) per high
power field (40! magnification) in each group. No patients with active ulcers were
included and no attempt to identify the type of leukocytes was made. The authors reported
that in patients with primary varicose veins, lipodermatosclerosis and healed ulceration
there was a median of 6, 45 and 217 WBCs per mm
2
respectively. This study demonstrated
a correlation between clinical disease severity and the number of leukocytes in the dermis
of patients with CVI.
The types of leukocytes involved in dermal venous stasis skin changes are con-
troversial. T-lymphocytes, macrophages and mast cells have been observed on immuno-
histochemical and electronmicroscopic examinations (39,40). The variation in types of
leukocytes observed may reflect the types of patients investigated. Wilkerson et al. biopsied
patients with erythematous and eczematous skin changes whereas Pappas et al. predomi-
nantly evaluated older patients with dermal fibrosis. Patients with eczematous skin changes
may have an autoimmune component to their CVI whereas patients with dermal fibrosis
may experience pathologic alterations consistent with chronic inflammation and altered
tissue remodeling (Fig. 3).
Extracellular Matrix Alterations
Once leukocytes have migrated into the extracellular space they localize around capillaries
and post-capillary venules. The perivascular space is surrounded by extracellular matrix
alterations (ECM) proteins and forms a perivascular “cuff.” Adjacent to these perivascular
cuffs and throughout the dermal interstitium is an intense and disorganized collagen
deposition (33,40). Perivascular cuffs and the accompanying collagen deposition are the
sine qua non of the dermal microcirculation in CVI patients (Fig. 4). The perivascular cuff
was originally thought to be the result of fibrinogen extravasation and erroneously referred
to as a “fibrin cuff.” It is now known that the cuff is a ring of ECM proteins consisting of
collagens type I and III, fibronectin, vitronectin, laminin, tenascin and fibrin (41). The role
of the cuff and its cell of origin is not completely understood. The investigation by Pappas
et al. suggested that the endothelial cells of the dermal microcirculation were responsible
for cuff formation (40). The cuff was once thought to be a barrier to oxygen and nutrient
diffusion however, recent evidence suggests that cuff formation is an attempt to maintain
vascular architecture in response to increased mechanical load (42). Although perivascular
cuffs may function to preserve microcirculatory architecture, several pathologic processes
may be related to cuff formation. Immunohistochemical analyses have demonstrated
transforming growth factor-b
1
(TGF-b
1
) and a
2
-macroglobulin in the interstices of peri-
vascular cuffs (43). It has been suggested that these “trapped” molecules are abnormally
distributed in the dermis leading to altered tissue remodeling and fibrosis. Cuffs may also
serve as a lattice for capillary angiogenesis explaining the capillary tortuosity and
increased capillary density observed in the dermis of CVI patients.
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Pathophysiology of Stasis Dermatitis and Dermal Fibrosis
The mechanisms modulating leukocyte activation, fibroblast function and dermal extra-
cellular matrix alterations have been the focus of investigation in the 1990s. CVI is a
disease of chronic inflammation due to a persistent and sustained injury secondary to
Figure 3 Electron micrograph (magnification 4300!) of mast cells (MC), macrophages (MP),
and Fibroblast (F) surrounding a central capillary from dermal biopsy of a patient with CEAP class 4
chronic venous insufficiency.
Pericapillary
Cuff
Migrating
Macrophages
Fibroblast
Postcapillary
Venule
Lymphatic
Figure 4 Electron micrograph (magnification 4300!) of a well-developed perivascular cuff in
close proximity to a fibroblast in a patient with CEAP class 6 chronic venous insufficiency. The long
arrow points to macrophages that appear to be entering a lymphatic lumen.
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venous hypertension. It is hypothesized that the primary injury is extravasation of
macromolecules (i.e., fibrinogen and a
2
-macroglobulin) and red blood cells (RBCs) into
the dermal interstitium (33,34,43–45). RBC degradation products and interstitial protein
extravasation are potent chemoattractants and presumably represent the initial underlying
chronic inflammatory signal responsible for leukocyte recruitment. It has been assumed
that these cytochemical events are responsible for the increased expression of ICAM-1
(intercellular adhesion molecule-1) on endothelial cells of microcirculatory exchange
vessels observed in CVI dermal biopsies (39,46). ICAM-1 is the activation dependent
adhesion molecule utilized by macrophages, lymphocytes and mast cells for diapedesis.
As stated above, all these cells have been observed by immunohistochemistry and electron
microscopy in the interstitium of dermal biopsies (39,40).
Cytokine Regulation and Tissue Fibrosis
Several authors have attempted to identify cytokines and growth factors involved in
the pathophysiology of CVI. As stated above, CVI is a chronic inflammatory disease
characterized by leukocyte recruitment, tissue remodeling and dermal fibrosis. These
physiologic processes are prototypical of disease states regulated by TGF-b
1
. TGF-b
1
is
present in pathologic quantities in the dermis of patients with CVI and increases with
disease severity (47). TGF-b
1
is secreted by interstitial leukocytes and bound to dermal
fibroblasts and extracellular matrix proteins (Figs. 3 and 5). Whether or not perivascular
cuffs bind TGF-b
1
is controversial (47).
The distribution and location of several other growth factors in the skin of CVI
patients has also been investigated. Peschen et al. reported on the role of platelet derived
growth factor receptor alpha and beta (PDGFR-a and b) and vascular endothelial growth
factor (VEGF) (48). These authors reported that PDGFR-a and b and VEGF expression
was strongly increased in the stroma of CVI patients with eczema and active ulcers
compared to patients with reticular veins and pigmentation changes only (48). To a lesser
degree, patients with lipodermatosclerosis demonstrated immunoreactivity to PDGFR-a
and b and VEGF as well. PDGFR-a and b expression was considerably elevated in the
capillaries and surrounding fibroblasts and inflammatory cells of venous eczema patients.
Figure 5 Immunohistochemistry (magnification 575!) of dermal skin biopsy demonstrating
transforming growth factor-b1 positive granules (long arrow) in leukocytes surrounding a peri-
vascular cuff and leukocytes migrating through a peri-vascular cuff (short arrow).
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In addition, immunoreactivity was increased in dermal fibroblasts, smooth muscle cells
and vascular cells of lipodermatosclerosis patients compared to patients with reticular
veins only. The greatest expression of PDGFR-a and b was observed in mesenchymal
cells and vascular endothelial cells of patients with active venous ulcers. VEGF
immunoreactivity correlated with disease severity. VEGF positive capillary endothelial
cells and pericapillary cells increased in patients with venous eczema, lipodermato-
sclerosis and active venous ulceration respectively. In a subsequent investigation, these
authors reported that with progression of CVI dermal pathology, the endothelial cell
adhesion molecules intercelluar and vascular adhesion molecules (ICAM-1, VCAM-1)
and their corresponding leukocyte ligands LFA-1 and VLA-4 increased (46). Based on
these observations, the authors speculated that leukocyte recruitment, capillary
proliferation and interstitial edema in CVI patients may be regulated through PDGF and
VEGF by upregulation of adhesion molecules leading to leukocyte recruitment, diapadesis
and release of chemical mediators (46).
In summary, the above investigations indicate that progression of CVI dermal
pathology is mediated by a cascade of inflammatory events. Venous hypertension causes
extravasation of macromolecules like fibrinogen and red blood cells which act as potent
inflammatory mediators. These mediators cause an upregulation of adhesion molecules
and the expression of growth factors like PDGF and VEGF which result in leukocyte
recruitment. Monocytes and mast cells travel to the site of injury which activate or release
TGF-b
1
and probably other undiscovered chemicals as well. What effect growth factor
binding has on fibroblast and endothelial cell function has been the focus of numerous
investigations in the 1990s.
Dermal Fibroblast Function
Several studies have reported aberrant phenotypic behavior of fibroblasts isolated from
venous ulcer edges when compared to fibroblasts obtained from ipsilateral thigh biopsies
of normal skin in the same patients. Hasan et al. reported that collagen production was
increased by 60% in a dose dependent manner in control fibroblasts whereas venous ulcer
fibroblasts were unresponsive. This unresponsiveness was associated with a fourfold
decrease in TGF-b
1
type II receptors (49). In a follow-up report, Kim et al. indicated that
the decrease in TGF-b
1
type II receptors was associated with a decrease in
phosphorylation of the TGF-b
1
receptor substrates SMAD 2 and 3 as well as p42/44
mitogen activated protein kinases (50). A similar investigation reported a decrease in
collagen production from venous ulcer fibroblasts and similar amounts of fibronectin
production when compared to normal controls (51).
Fibroblast responsiveness to growth factors was further delineated by Stanley
et al. (52). These investigators reported that venous ulcer fibroblast growth rates were
markedly suppressed when stimulated with bFGF, EGF and IL-1b. In a follow-up
investigation these authors noted that the previously observed growth inhibition could
be reversed with bFGF (53). Lal et al. reported that the proliferative responses of CVI
fibroblasts to TGF-b
1
, correlated with disease severity (54). Fibroblasts from patients
with CEAP class 2–3 disease retain their agonist induced proliferative capacity. Class 4
and 5 fibroblasts demonstrated diminished agonist induced proliferation whereas class 6
(venous ulcer fibroblasts) did not proliferate after TGF-b
1
stimulation confirming the
observations made by previous investigators. Phenotypically, venous ulcer fibroblasts
appear morphologically similar to fibroblasts undergoing cellular senescence. Therefore,
the blunted growth response of CVI venous ulcer fibroblasts appears related to the
development of cellular senescence (52,55).
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Other characteristics of senescent cells are an overexpression of matrix proteins such
as fibronectin (cFN) and enhanced activity of b-galactosidase (SA-b-Gal). In an evaluation
of seven patients with venous stasis ulcers, it was noted that a higher percentage of SA-b-
Gal positive cells in venous ulcers compared to normal controls (6.3% vs. 0.21%, p 0.0.6)
(53). It was also reported that venous ulcer fibroblasts produced one to four times more
cFN by western blot analysis compared to controls (55). These data support the hypothesis
that venous ulcer fibroblasts phenotypically behave like senescent cells. However,
senescence is probably the end manifestation of a wide spectrum of events that leads
to proliferative resistance and cellular dysfunction. Diminished telomere length and
telomerase activity are the sine qua non of truly senescent cells. To date, there are no
reported studies indicating an abnormality in CVI fibroblast telomere length or telomerase
activity. Absent these investigations, the true role of senescence in CVI remains ill-
defined.
Role of Matrix Metalloproteinases and Their Inhibitors in CVI
The signaling event responsible for the development of a venous ulcer and the mechanisms
responsible for prolonged wound healing are poorly understood. Wound healing is an
orderly process that involves inflammation, re-epithelialization, matrix deposition and
tissue remodeling. Tissue remodeling and matrix deposition are processes controlled by
matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases
(TIMPs). In general, MMPs and TIMPs are not constitutively expressed. They are induced
temporarily in responseto exogenous signals such as various proteases, cytokinesor growth
factors, cell–matrix interactions and altered cell–cell contacts. TGF-b
1
is a potent inducer
of TIMP-1 and collagen production and inhibitor of MMP-1 through regulation of gene
expression and protein synthesis. Several studies have demonstrated that prolonged and
continuous TGF-b
1
production causes tissue fibrosis by stimulating ECM production
and inhibiting degradation by affecting MMP and TIMP production. Alterations in MMP
and TIMP production may similarly modulate the tissue fibrosis of the lower extremity in
CVI patients. Several investigators have reported that the gelatinases MMP-2 and 9 as well
as TIMP-1 are increased in the exudates of patients with venous ulcers compared to acute
wounds (56–58). However, analyses of biopsy specimens have demonstrated variable
results. Herouy et al. reported that MMP-1,2 and TIMP-1 are increased in patients with
lipodermatosclerosis compared to normal skin (59). In a subsequent investigation, biopsies
from venous ulcer patientswere found to have increased levels of the activeform of MMP-2
compared to normal skin (60). In addition, increased immunoreactivity to EMMPRIN
(Extracelluar inducer of MMP), MT1-MMP (Membrane Type 1) and MT2-MMP in the
dermis and perivascular regions of venous ulcers (61). Saito et al. were unable to identify
differences in overall MMP-1, 2, 9 and TIMP-1 protein levels or activity in CVI patients
with CEAP class 2 through 6 disease compared to normal controls or CVI groups (62).
However, within a clinical class, MMP-2 levels were elevated compared to MMP-1, 9 and
TIMP-1 in patients with class 4 and class 5 disease. These data indicate that active tissue
remodeling is occurring in patients with CVI. Which matrix metalloproteinases are
involved and how they are activated and regulated is currently unclear. It appears that
MMP-2 may be activated by urokinase plasminogen activator (uPA). Herouy et al. observed
increased uPA and uPAR mRNA and protein levels in patients with venous ulcers compared
to normal skin (63). The elevated levels of active TGF-b
1
in the dermis of CVI patients
suggests a regulatory role for TGF-b
1
in MMP and TIMP synthesis and activity. However,
there is currently no direct evidence indicating such a relationship.
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CONCLUSION
The mechanisms regulating varicose vein development and the subsequent dermal skin
sequelae caused by chronic ambulatory venous hypertension have only recently been
investigated. It is clear that varicose vein formation has a genetic component that is linked
to environmental stimuli. Susceptible patients develop vein wall fibrosis and loss of
valvular competence that lead to venous hypertension. The transmission of high venous
pressures to the dermal microcirculation causes extravasation of macromolecules and red
blood cells that serve as the underlying stimulus for inflammatory injury. Activation of the
microcirculation results in cytokine and growth factor release leading to leukocyte
migration into the interstitium. At the site of injury, a host of inflammatory events is set
into action. TGF-b
1
appears to be a primary regulator of CVI induced injury. TGF-b
1
secretion from leukocytes with subsequent binding to dermal fibroblasts is associated with
intense dermal fibrosis and tissue remodeling. In addition, decreased TGF-b
1
type II
receptors on venous ulcer fibroblasts, are associated with diminished fibroblast
proliferation. Fibroblast proliferation diminishes with disease progression ultimately
leading to senescence and poor ulcer healing. In addition, increases in MMP-2 synthesis,
appear to increase tissue remodeling and further impede ulcer healing. As our
understanding of the underlying cellular and molecular mechanisms that regulate CVI
and ulcer formation increase, improved therapeutic interventions for treatment and
prevention will ultimately follow.
KEY POINTS
† It seems probable that varicose vein formation has a genetic component that is
linked to environmental stimuli.
† The relevant gene(s) have not yet been identified.
† DVT results in valvular destruction and sustained venous hypertension.
† In chronic venous insufficiency (CVI) there is actually increased venous flow
rather than stagnation.
† Pericapillary fibrin cuffs exist but have never been demonstrated to act as a
barrier to nutrient flow or oxygen diffusion.
† The signaling events responsible for the development of a venous ulcer and the
mechanisms responsible for prolonged wound healing are still poorly under-
stood.
† The transmission of high venous pressures to the dermal microcirculation causes
extravasation of macromolecules and red blood cells that serve as the underlying
stimulus for inflammatory injury.
† At the site of injury, a host of inflammatory events is set into action.
† Activation of the microcirculation results in cytokine and growth factor release
leading to leukocyte migration into the interstitium causing local injury.
† TGF-b
1
appears to be a primary regulator of CVI induced injury.
† Fibroblast proliferation diminishes with disease progression ultimately leading
to senescence and poor ulcer healing.
† Increase in MMP-2 synthesis appear to increase tissue remodeling and further
impede ulcer healing.
† A deeper understanding of the mechanism involved in CVI may lead to new
treatment strategies in the future.
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