JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2015, 66, 6, 841-846
www.jpp.krakow.pl
M.A. DEJA1, M. MALINOWSKI1, K.S. GOLBA2, M. PIEKARSKA1, S. WOS1
PERIVASCULAR TISSUE MEDIATED RELAXATION A NOVEL PLAYER IN HUMAN VASCULAR TONE REGULATION
1
Department of Cardiac Surgery, Medical University of Silesia, School of Medicine in Katowice, Poland; 2Department of
Electrocardiology and Heart Failure, Medical University of Silesia, School of Health Sciences in Katowice, Poland
Perivascular tissue (PVT) modulates vascular tone, releasing adventitia/adipocyte derived relaxing factor (ADRF). Its
physiological role remains unclear. We studied isolated internal thoracic artery (ITA) segments obtained from 132
patients subjected to coronary artery bypass grafting. The vessels were skeletonized in vitro and the ITA rings and PVT
were incubated in separate isolated organ baths. Skeletonized ITA segments were first precontracted with 10–5.5mol/L 5hydroxytryptamine hydrochloride. The PVT was next transferred to the ITA tissue bath. This resulted in relaxation of
ITA, presumably related to ADRF release from PVT which was floating freely in the tissue bath. The in-vitro relaxation
responses were then correlated to patients’ characteristics - including demographics, clinical and laboratory data, as well
as therapy. Perivascular tissue transfer resulted in 49.7 ± 26.2% relaxation of precontracted ITA segments. In multiple
linear regression modelling, the relaxation of ITA to PVT was negatively related to patient age (β = –0.67; 95% CI –1.17
– –0.17; P = 0.009), symptoms of CCS class 4 angina (β = –20.11; 95%CI –32.25 – –7.97; P = 0.001), and positively
to body mass (β = 0.37; 95%CI 0.08 – 0.67; P = 0.01) and lack of heart failure symptoms (NYHA class 1) (β = 9.06;
95%CI 0.33 – 17.79; P = 0.04). The relaxation response to PVT was not related to patients’ sex, diabetes, hypertension,
lipid profile or therapy in both univariate and multivariate analysis. PVT might play an important role in regulating
vascular tone in humans as exemplified by its changing physiological function with age and in atherosclerosis.
K e y w o r d s : arteries, vasodilatation, aging, perivascular tissue, atherosclerosis, adventitia/adipocyte derived relaxing factor,
internal thoracic artery
INTRODUCTION
Perivascular tissue (PVT) plays a role in modulation of
vascular function, which is not yet fully elucidated. PVT
surrounds most of the systemic vessels, producing a number of
adipokines with vasoactive properties, and currently unidentified
adventitia/adipocyte derived relaxing factor (ADRF). A number
of compounds have been proposed as ADRF candidates,
including methyl palmitate (1), cystathionine-γ-lyase derived
H2S (2, 3) and angiotensin 1-7 (4). ADRF induces endotheliumindependent vasorelaxation that is mediated via the opening of
specific types of K+ channels in various animal species. PVTderived ADRF have been examined in Wistar Kyoto rats,
Sprague Dawley rats, spontaneous hypertensive rats (4-9),
lipoatrophic mice (10, 11), pigs (12) and human models in vitro
(13-17). Results on the specific types of K+ channels involved in
the relaxation response induced by perivascular adipose tissue
(PVAT) vary depending on the vessel type and animal origin.
Recent studies showed that the ability of ADRF to modulate
vascular function was altered in obese rats (8), rats with increased
blood pressure induced by perinatal exposure to nicotine (18), in
diabetic rats (4) and in hypertensive mice born without white
adipose tissue (10). However, research on physiological variability
of PVT dependent relaxation in humans is remarkably limited (19).
We assessed anticontractile properties of PVT of human
internal thoracic artery (ITA), and the association between PVT
function and clinical characteristics of the patients.
MATERIAL AND METHODS
Patients and material
To study the influence of various clinical factors on
anticontractile properties of human PVT, we retrospectively
analysed in vitro experiments on isolated segments of human
internal thoracic artery (ITA) and its PVT, performed previously in
our laboratory. The in vitro experiment described below formed an
initial part of numerous protocols aimed at elucidating the
mechanisms of action of putative ADRF in human vasculature. The
patient related variables were collected prospectively at the time of
surgery. However, some data (e.g. lipidograms) were not available
in all patients, as the study was conceived after data collection.
The study was performed on isolated segments of left human
ITA discarded after the conduit had been trimmed to the length
necessary for grafting. The study complies with the Declaration
of Helsinki. The Local Research Ethics Committee agreed to the
use of discarded human tissue for the experimental work and the
842
patients’ informed consent was waived. These arterial segments
were obtained from patients undergoing surgery for stable
isolated coronary artery disease. All grafts were harvested
pedicled in a standard fashion using electrocautery. The ITA
fragments were placed in cold (4°C) calcium-free modified
Krebs-Henseleit solution: NaCl, 123.0; KCl, 4.70; MgSO4, 1.64;
NaHCO3, 24.88; KH2PO4, 1.18; glucose, 5.55; sodium pyruvate,
2.0 (mmol/L) and transferred immediately to the laboratory.
Experimental procedures
In the laboratory, the vessel was freed from all surrounding
perivascular tissue. It was next divided into 3 mm long segments.
The arterial rings were suspended on stainless steel wire hooks in
the organ bath chamber filled with oxygenated (95% O2, 5%
CO2) Krebs-Henseleit solution of the following composition:
NaCl, 119.0; KCl, 4.70; CaCl2, 1.6; MgSO4, 1.2; NaHCO3, 25.0;
KH2PO4, 1.2; glucose, 11.01; sodium pyruvate, 2.0 (mmol/L);
(pH 7.4). The temperature was maintained at 37°C. The Schuler
isolated organ bath (Hugo Sachs Elektronik (HSE); MarchHugstetten, Germany) was used. Vessel wall tension was
measured with isometric force transducer F30 (HSE). This signal
was enhanced with a bridge amplifier Type 336 (HSE) and
recorded using PowerLab/4SP system and Chart software (AD
Instruments, Chalgrove, Oxfordshire, UK). The perivascular
tissue was incubated separately in oxygenated Krebs-Henseleit
solution of the same composition, and washed several times.
After the short period of initial incubation the vessel wall
tension and diameter were normalized in a standardized procedure
as described by Mulvany and Halpern (20). This way, every vessel
ring was set to 90% of the diameter it would have had in vivo when
relaxed and under the transmural pressure of 100 mmHg, using the
Laplace law; P = 2T/d. After equilibration the vessel was left for 30
min to stabilize, during which the tissue was thoroughly washed.
The vessel responsiveness was initially tested with repeated
exposure to 60 mmol/L of KCl, with subsequent washout. This
model is widely used in laboratories (2, 6, 14-17, 21).
Next, the artery was precontracted with 10–5.5mol/L
serotonin (5-hydroxytryptamine hydrochloride, Sigma Aldrich).
After the plateau of contraction had been achieved, the PVT was
transferred to the organ chamber. As the PVT was freely floating
in the tissue bath, subsequent relaxation must have been
produced by a soluble factor released by PVT, as described
previously (15, 20).
The contraction produced by serotonin was measured as the
change of vessel wall tension from the baseline level, and
expressed in mN. The degree of relaxation produced by
transferring PVT to the organ bath was assessed in relation to
preceding contraction and expressed as a percentage. The
schematic of the experiment is shown in Fig. 1. The
anticontractile effect of PVT was related to patient demographic,
clinical characteristics, laboratory biochemical data and therapy.
If more than one ITA segment coming from the same patient was
studied, the median relaxation was calculated and every patient
was included only once in the analysis.
Statistical analysis
Continuous variables were presented as mean ± standard
deviation, and frequencies as percentages. The estimated
relaxation to PVT in various subgroups was presented as mean
with 95% confidence interval. The normal distribution of
relaxation responses was confirmed with Kolmogrov Smirnov
test. The relaxation responses in various subgroups were
Fig. 1. Illustration of experimental setup and bioassay protocol. The experiments were performed in tissue baths using 3 mm internal
thoracic artery ring(s) obtained during coronary bypass surgery and skeletonized in vitro. Perivascular tissue (PVT) remaining from
skeletonisation was incubated separately in oxygenated Krebs-Henseleit solution. The artery was precontracted with 10–5.5mol/L
serotonin (5-HT) (1). After the plateau of contraction had been achieved the PVT was transferred to the organ chamber (2). This
resulted in various degree of vasorelaxation.
843
compared using Student’s t test or analysis of variance with
Holmes-Sidak test for post-hoc comparisons. To correlate
relaxation with continuous variables, Pearson Product Moment
or Spearman Rank Order correlation was used depending on
distribution of the data.
For the sake of multivariable analysis, the continuous
variables not fulfilling the assumption of normal distribution were
log transformed, and ordinal variables (CCS and NYHA classes)
were dichotomized. The multiple linear regression model was
constructed using backward imputation method, and included
only the variables with P value < 0.1. In all analyses P < 0.05 was
considered statistically significant. All analyses were performed
using SigmatPlot 12.0 (Systat Inc., San Jose, CA) and SPSS 14.0
(SPSS Inc. Chicago, USA) Software.
RESULTS
We analysed 157 preparations from 132 patients. The
majority of patients (73%) were male. Mean age was 65.0 ± 8.5
years. The baseline characteristics of patients are detailed in
Table 1. Preoperative medication is summarized in Table 2.
Serotonin (10–5.5mol/L) contracted skeletonized segments of
ITA by 51.6 ± 39.2 mN. The transfer of perivascular tissue
remaining after skeletonisation to the ITA tissue bath caused
relaxation of 49.7 ± 26.2%. The mean weight of PVT was 701 ±
480 mg. Fig. 1 shows a sample of original tension recording.
Table 1. Baseline characteristics of the patients (n = 132).
Variables
Age, years
Female gender, n(%)
Body weight, kg
Height, cm
Body mass index, kg/m2
LVEF, %
Diabetes mellitus, n(%)
on insulin
Arterial hypertension, n(%)
Angina, n(%)
CCS class 0
CCS class 1
CCS class 2
CCS class 3
CCS class 4
Dyspnoea, n(%)
NYHA class 1
NYHA class 2
NYHA class 3
NYHA class 4
Triglycerides (n = 79), mg/dl
Total cholesterol (n = 79 ), mg/dl
HDL cholesterol (n = 79), mg/dl
LDL cholesterol (n = 79), mg/dl
Creatinine, mg/dl
eGFR, ml/min/1.73m2
65.0 ± 8.5
35 (27%)
80.4 ± 14.1
169.3 ± 7.3
27.7 ± 3.9
50.7 ± 9.8
48 (36%)
21 (16%)
115 (87%)
4 (3%)
25 (19%)
43 (33%)
43 (33%)
17 (13%)
82 (62%)
37 (28%)
11 (8%)
2 (2%)
135.2 ± 65.8
175.2 ± 51.6
47.8 ± 14.4
102.9 ± 42.1
0.92 ± 0.23
81.9 ± 17.8
BMI, body mass index; CCS, Canadian Cardiovascular Society;
eGFR, estimated glomerular filtration rate; LVEF, left
ventricular ejection fraction; NYHA, New York Heart
Association.
Continues variables are presented as mean ± standard deviation.
The relaxation of serotonin precontracted ITA segments in
response to PVT did not differ between gender (female 43.8%,
95% CI 36.8 – 50.8% vs. men 51.0%, 95% CI 45.4 – 56.6%;
P = 0.2). However, it was negatively related to patient age (r =
–0.34; P < 0.001). At the same time the relaxation was positively
correlated with patient body mass, height and BMI (Table 3).
The relaxation response was similar in ITA segments coming
from diabetic 45.9% (95% CI 38.3 – 53.6%) and non-diabetic
50.9% (95%CI 45.3 – 56.6%) patients (P = 0.3), as well as
hypertensive 50.1% (95% CI 45.2 – 54.9%) and nonhypertensive 42.5% (95% CI 29.8 – 55.3%) patients (P = 0.3).
Fig. 2 shows the influence of patients’ angina and dyspnoea
on ITA relaxation in response to PVT. Importantly, ITA relaxation
to PVT was less pronounced in patients with angina CCS class 4.
For further analysis, we contrasted the relaxation responses in
patients with class 4 angina, which were relatively weak (28.8%
95% CI 12.8 – 44.8%), with better responses in other patients
(52.1% 95% CI 47.7 – 56.6%; P < 0.001). Similarly, we
contrasted relaxation to PVT in ITAs from patients with NYHA
class 1, which were very good, with all other ITA segments.
We found no influence of lipid fraction level on ITA
responses to PVT (Table 3). We have, however, found weak
positive correlation between relaxation in response to PVT and
patient estimated glomerular filtration rate.
Table 2. Preoperative medication.
Beta blockers, n(%)
ACE inhibitors
ARB
Aldosterone antagonists
Diuretics
Nitrates
Calcium antagonists
HMG-CoA inhibitors
N=132
108 (82%)
65 (47%)
4 (3%)
31 (24%)
17 (13%
67 (51%)
48 (36%)
78 (59%)
ACE, angiotensin converting enzyme; ARB, angiotensin
receptor blockers; HMG CoA, 3-hydroxy-3-methyl-glutaryl
coenzyme A.
Table 3. Correlation of the relaxation response of internal
thoracic artery to perivascular tissue and patient characteristics
(continues variables).
Age
Body mass
Height
Body mass index (per 1kg/m2)
LVEF
Creatinine
eGFR
Triglycerides
Total cholesterol
HDL cholesterol
LDL cholesterol
Mass of PVT
r
–0.34
0.27
0.23
0.18*
0.15*
–0.21*
0.20*
0.12*
–0.02*
0.08*
–0.10*
0.11*
P
<0.001
0.002
0.009
0.04
0.096
0.8
0.02
0.3
0.9
0.5
0.4
0.2
eGFR, estimated glomerular filtration rate; LVEF, left
ventricular ejection fraction; PVT, perivascular tissue; r, Pearson
Product Moment correlation coefficient, or Spearman Rank
Order correlation coefficient (*) are given where appropriate.
844
Fig. 2. The influence of patient angina (A) and dyspnoea (B) on internal thoracic artery relaxation to perivascular tissue.
Mean values are presented as dots. Whiskers represent the 95% confidence interval values.
P in box comes from ANOVA; p above data comes from post-hoc analysis.
CCS, Canadian Cardiovascular Society; NYHA, New York Heart Association.
Fig. 3. The correlation between relaxation of internal thoracic
artery to perivascular tissue and patient age. r, Pearson product
moment correlation coefficient. The linear regression line with
95% confidence limits and prediction limits are shown.
We failed to document influence of patient therapy on
relaxation of his/her ITA segments to PVT (Table 4).
No correlation of relaxation response with PVT mass was
found. (Table 3). On multiple linear regression analysis we
found that ITA relaxation to PVT was independently negatively
associated with patients’ age and CCS class 4 angina (Fig. 3). On
the other hand it was positively associated with patients’ body
mass and the lack of heart failure symptoms (NYHA class 1).
(Table 5).
DISCUSSION
The major finding of our study is that the anticontractile
properties of human PVT depend on many physiologically
relevant factors. The fact that PVT dependent relaxation,
attributed to putative ADRF release, varies with age, obesity,
diabetes, hypertension etc. was confirmed in animal models and
served as evidence of its physiological role. Our study is the first
to examine such relationships in humans, and we believe it
constitutes a proof, that PVT releasing ADRF plays a major role
in human physiology.
The major factor limiting anticontractile properties of ITA’s
PVT in our study is patient age. This parallels the findings of
Fesus at al. who showed that anticontractile properties of
perivascular fat decrease with age in New Zealand Obese mice,
in spite of increasing amount of visceral fat tissue (22). The same
is true with regard to one of the candidates for ADRF, hydrogen
sulphide, production of which from PVT decreases with age (2).
Meanwhile, age dependent decrease in endothelium dependent
vasorelaxation has long been recognized (23-26).
Decreased ADRF release from PVT has been proposed as
one of the factors playing a role in the development of
hypertension, based on animal studies (10, 27). We failed to
show a relationship between arterial hypertension and
anticontractile effect of PVT in ITA segments. This may be
related to the fact that nearly all of our patients had a history of
hypertension. Additionally they were all treated, and
antihypertensive therapy may improve ADRF release (1, 29, 30).
One of the findings of our study is that PVT of patients with
higher body mass showed stronger anticontractile properties.
This is in agreement with the fact that ADRF was virtually
absent in lipoatrophic mice (10). These mice are known to
develop diabetes, hyperinsulinaemia, hypertension and
myocardial hypertrophy, suggesting that perivascular adipose
tissue is beneficial for cardiovascular function (10, 30). On the
other hand, obesity results in diminished anticontractile
properties of PVT as demonstrated in New Zealand obese mice
mesenteric artery (22), or in rat aorta (8-10, 18). In fact,
anticontractile properties of PVT were diminished in metabolic
syndrome in comparison with healthy volunteers, as assessed in
human small arteries preparation from subcutaneous gluteal fat
(19). We believe that the plausible explanation of our finding,
rather than sticking to “the fatter the better” hypothesis (31),
might be that the ITA pedicle of “heavier” patients contained
more adipose tissue, while that of the lean patients was more
845
Table 4. Influence of patients preoperative therapy on the relaxation response of internal thoracic artery to perivascular tissue.
Beta blockers
ACE inhibitors or ARB
Calcium antagonists
Nitrates
Diuretics
Aldosterone antagonists
HMG CoA inhibitors
Insulin
Therapy
50.0 (45.0 – 54.9)
51.7 (45.5 – 57.8)
43.6 (35.7 – 51.5)
47.7 (41.6 – 53.8)
41.6 (30.4 – 52.9)
46.3 (35.6 – 57.0)
49.4 (43.2 – 55.6)
40.4 (26.7 – 54.2)
Without therapy
45.3 (33.9 – 56.6)
46.3 (39.7 – 53.0)
52.3 (46.8 – 57.7)
50.6 (43.8 – 57.3)
50.2 (45.3 – 55.1)
50.0 (45.0 – 55.0)
48.6 (42.0 – 55.3)
50.8 (46.0 – 55.5)
P
0.4
0.2
0.07
0.5
0.2
0.5
0.9
0.097
ACE, angiotensin converting enzyme; ARB, angiotensin receptor blockers; HMG, CoA-3-hydroxy-3-methyl-glutaryl coenzyme A.
Data are presented as mean and 95% Confidence Intervals. P from Student’s t test.
Table 5. Predictors of internal thoracic artery relaxation response to perivascular tissue in Multiple Linear Regression Analysis.
tissue in Multiple Linear Regression Analysis.
Standardized
ȕ
95% CI
P
coefficient ȕ
(Constant)
59.82
16.15 – 103.49
0.008
Age
–0.67
–1.17 – –0.17
–0.22
0.009
CCS class 4 angina
–20.11
–32.25 – –7.97
–0.26
0.001
Body mass
0.37
0.08 – 0.67
0.20
0.01
NYHA class 1 dyspnoea
9.06
0.33 – 17.79
0.17
0.04
CCS, Canadian Cardiovascular Society; NYHA, New York Heart Association.
fibromuscular. However, this is speculation, as we did not
perform histological studies of the ITA pedicles of our patients.
A very interesting result of our study is the severely
depressed anticontractile effect of PVT obtained from patients
with the most advanced ischemic symptoms. Findings of
Greenstein at al. in metabolic syndrome correspond well with
this result. Also, inflammatory reaction and the dysfunction of
perivascular adipose tissue occur in the development of
atherosclerosis (17, 32-35). Therefore, although no animal
studies directly relate to our finding, it seems to fit well with
current thought on the role of perivascular tissue in
atherosclerosis.
It may appear strange that we failed to find correlation of PVT
mass with the relaxation of precontracted ITA. On the other hand,
no other study showed that the anticontractile effect depended on
the mass of PVT. The dose-effect relationship for ADRF effect
was demonstrated when using aliquots from PVT incubated in
separate tissue bath (6, 7). Similar findings were reproduced in our
laboratory (unpublished data), but we elected to transfer the PVT
itself, rather than the aliquots, on the presumption that it would
produce maximal possible anticontractile effect on every
occasion. It seemed likely, as the PVT mass in our experiments
was several times higher than the PVT mass used in animal
experiments (9). We simply used all the tissue that constituted the
ITA pedicle left after dissecting the ITA segment free. As
mentioned above, we did not conduct any histological
morphometric studies to assess the content of the pedicle, yet we
presumed that the tissue used was always in excess of what was
necessary to elicit maximal anticontractile effect.
The obvious limitation of our study stems from the fact that
we studied human tissue coming from the patients subjected to
cardiac surgery. As a consequence, we have to accept a myriad
of various factors that might influence vascular function. They
might include various disease states in different stages of
progression, as well as their therapy, consisting of varying agents
in many dosages. Simply put, no human experimental study can
be as methodologically “clean” as an animal model. We have to
rely on multivariable analysis to try and dissect real
relationships. We have to accept that the correlations will never
appear as unambiguous as they might in prospectively designed
animal experiments.
Bearing the limitations in mind we believe, that our study
demonstrates, that PVT might play an important role in
regulating vascular tone in humans. We show that its function
changes with age and in coronary artery disease and may well be
affected by other factors.
Acknowledgments: We would like to thank Ms. Anna Urdzon
for her superb technical assistance and the whole staff from the
Department of Cardiac Surgery for the help in collecting ITAs
from the patients. We appreciate editorial help of Piers Murphy
(Emmanuel College, The University of Cambridge).
This work was supported by Ministry of Science and Higher
Education grant, NN 403 088335 and statutory funds of the
Medical University of Silesia.
Conflict of interests: None declared.
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R e c e i v e d : November 10 2014
A c c e p t e d : October 24, 2015
Author’s address: Prof. Marek A. Deja, Department of
Cardiac Surgery, Medical University osf Silesia, 45-47 Ziolowa
Street, 40-635 Katowice, Poland
E-mail: [email protected]