The significance of CD105, TGFβ and CD105/TGFβ complexes in coronary artery disease

doi:10.1016/S0021-9150(99)00476-1

Atherosclerosis

Volume 152, Issue 1, 1 September 2000, Pages 249-256

https://doi.org/10.1016/S0021-9150(99)00476-1 Get rights and content

Abstract

We have quantified levels of CD105, its ligand TGFβ and receptor-ligand complexes in sera from healthy individuals (n=31), patients with triple vessel disease documented by coronary angiography (TVD; n=36) and patients with chest pain and a positive exercise electrocardiogram but with normal coronary angiogram (NCA; n=30). Both active TGFβ1 and active plus acid-activatable TGFβ1 [(a+l)TGFβ1] were significantly depressed in patients with TVD compared with the other two groups (P≤0.04). CD105 levels in TVD patients were also diminished but elevated in NCA patients. In contrast, patients with TVD had more CD105/TGFβ1 complex in their sera than the other two groups, suggesting that this may be the reason why TVD patients had low levels of receptor and ligand. TGFβ3 levels were similar in the three groups, but elevated CD105/TGFβ3 levels were noted in patients with NCA compared with those with TVD and healthy individuals (P≤0.02). CD105 was correlated with both active TGFβ1 and (a+l)TGFβ1 (P=0.02). CD105 also strongly correlated with TGFβ3 and CD105/TGFβ3 complexes (P=0.001 in both cases). The changes in levels of CD105, TGFβ1 and the receptor-ligand complexes in sera of patients with atherosclerosis suggest that these molecules may be important in the pathobiology of the atherosclerotic disease. Further studies on sequential samples from a larger cohort of patients are needed to define a causal relationship between these molecules and the disease progression.

Introduction

The role of endothelial dysfunction in initiating atherosclerosis is an active area of investigation, because it may reflect the global functional state of vascular disease and thereby help define subjects at increased coronary risk. Circulating markers of endothelial damage, such as von Willebrand factor (vWF) [1], vascular cell adhesion molecule-1 (VCAM-1) [2] and plasminogen activator inhibitor-type 1 (PAI-1) [3] have been shown to be altered in patients with vascular disease. While these factors may be significant through being involved in atherosclerosis, there is little definitive evidence to support a correlation with the progression of the disease. CD105 (endoglin) is a homodimeric transmembrane receptor for TGFβ1 and TGFβ3, which is particularly abundant in vascular endothelial cells (ECs) [4]. Markedly increased expression of this receptor has been demonstrated in activated endothelial cells following irradiation [5] and in tissues undergoing angiogenesis [6], [7], [8], [9], [10]. These observations suggest that CD105 may be a novel potential marker for endothelial damage/repair and activation. Although no signal sequence has been identified in CD105 protein, the constitutive phosphorylation of the cytoplasmic domain and the formation of the heteromeric complex of CD105 with the TGFβ RI-RII signal complex in endothelial cells implies the involvement of CD105 in modulating TGFβ signalling [11].

The role of TGFβ in the pathobiology of atherosclerosis is being increasingly recognised. Its functional regulation of the vessel wall is by its direct effect on the vascular smooth muscle cells (VSMCs), endothelial cells and extracellular matrix (ECM). In addition, TGFβ has a number of other functions including suppression of immune responses [12] and reduction of superoxide anions [13], which are considered to be important in atherogenesis. TGFβ1 and TGFβ3, although share 70% homology, exhibit distinct functions in a range of pathobiological situations, such as wound healing, radiation-induced tissue damage and tumour development [14], [15], [16]. What functional role the two isoforms play in coronary artery disease (CAD) is not known.

Previously two independent studies have reported that CD105 is raised in patients with peripheral vascular disease [17] and TGFβ1 levels are depressed in patients with atherosclerosis [18]. However, no information is available in the same cohort of patients about the possible relationship of soluble CD105, TGFβ and the CD105/TGFβ complexes. VSMCs participate in the development and progression of atherosclerosis through their migration, proliferation and secretion of ECM. Each of these aspects of VSMC behaviour can be modified by TGFβ. A recent finding, which demonstrated the existence of CD105 mRNA and protein in human VSMCs [19], leads to the speculation that in addition to endothelial cells, it may modulate effects of TGFβ on VSMCs. Based on these findings, we hypothesised that the interaction of CD105 with TGFβ might affect the bioavailability of TGFβ and hence contribute to the progression of CAD. To examine this hypothesis, in this study we have examined circulating levels of CD105, TGFβ and the CD105/TGFβ complexes in healthy individuals, in patients with established triple vessel coronary artery disease and a group with normal angiograms but with continued chest pain and positive exercise electrocardiogram.

Section snippets

Subjects

Two groups of patients were recruited for this study which had ethics committee approval. One group of patients had significant coronary artery disease in all three coronary arteries on coronary angiograms (TVD). Significant coronary artery disease was defined as a reduction of more than 50% in the intraluminal diameter of the coronary artery. The second group were patients who had continued chest pain suggestive of angina pectoris, a positive exercise electrocardiogram but normal coronary

Clinical data of the subjects

A summary of data related to the clinical tests and some risk factors are presented in Table 1. Compared to normal individuals, both groups of patients with ischemic heart disease (IHD) had higher total and LDL-cholesterol and triglyceride concentration, and lower HDL-cholesterol levels (P in all cases was ≤0.01). Patients with triple vessel disease had lower levels of HDL-cholesterol compared to patients with normal coronary angiograms (P≤0.01).

Quality assessment of the ELISAs

The quality of the immunoassays was assessed by

Discussion

The observation that patients with coronary artery atherosclerotic disease have significantly depressed levels of TGFβ1 is consistent with the report by Grainger et al. [18], who have suggested that it is a potential cardiovascular protector. The elevated levels of CD105/TGFβ1 complex seen in the present study in patients with TVD indicate an increased interaction between CD105 and TGFβ1. This could be the reason why CD105 and TGFβ1 levels were decreased in these patients. The lack of a

Acknowledgements

CGL is a Wellcome Trust fellow.

References (30)

A.D. Blann et al.
von Willebrand factor, endothelial cell damage and atherosclerosis
Eur. J. Vasc. Surg.
(1994)
H.F. Rulo et al.
Expression of endoglin in psoriatic involved and uninvolved skin
J. Dermatol. Sci.
(1995)
H. Yamashita et al.
Endoglin forms a heteromeric complex with the signalling receptors for transforming growth factor-β
J. Biol. Chem.
(1994)
J. Massague et al.
The TGFβ family and its composite receptors
Trends Cell. Biol.
(1994)
A.D. Blann et al.
Serum levels of the TGFβ receptor are increased in atherosclerosis
Atherosclerosis
(1996)
P.J. Adam et al.
Expression of endoglin mRNA and protein in human vascular smooth muscle cells
Biochem. Bioph. Res. Co.
(1998)
D.J. Grainger et al.
Active and acid-activatable TGFβ in human sera, platelets and plasma
Clin. Chim. Acta
(1995)
J.M. Wang et al.
Quantitation of endothelial cell specific protein E9 employing a single monoclonal antibody in an indirect sandwich ELISA
J. Immunol. Methods
(1994)
C.G. Li et al.
Immunodetection and characterisation of soluble CD105-TGFβ complexes
J. Immunol. Methods
(1998)
S. Schultz-Cherry et al.
Thrombospondin binds and activates the small and large forms of latent transforming growth factor β in a chemically defined system
J. Biol. Chem.
(1994)

R. de Caterina et al.

Soluble vascular cell adhesion molecule-1 as a biohumoral correlate of atherosclerosis

Arterioscler. Thromb. Vasc. Biol.

(1997)

D. de Bono

Significance of raised plasma concentrations of tissue type plasminogen activator and plasminogen activator inhibitor in patients at risk from ischaemic heart disease

Br. Heart. J.

(1994)

S. Kumar et al.

CD105 and angiogenesis

J. Path.

(1996)

J.M. Wang et al.

Irradiation induces up-regulation of E9 protein in human vascular endothelial cells

Int. J. Cancer.

(1995)

J.M. Wang et al.

Breast carcinoma: comparative study of tumour vasculature using two endothelial cell markers

J. Natl. Cancer Inst.

(1994)

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Endoglin, alias CD105, is a human membrane glycoprotein highly expressed in vascular endothelial cells. It is involved in angiogenesis and angiogenesis-related diseases, including the rare vascular pathology known as hereditary hemorrhagic telangiectasia type 1. Although endoglin acts as an accessory receptor for members of the transforming growth factor-β family, in recent years, emerging evidence has shown a novel functional role for this protein beyond the transforming growth factor-β system. In fact, endoglin has been found to be an integrin counterreceptor involved in endothelial cell adhesion processes during pathological inflammatory conditions and primary hemostasis. Furthermore, a circulating form of endoglin, also named as soluble endoglin, whose levels are abnormally increased in different pathological conditions, such as preeclampsia, seems to act as an antagonist of membrane-bound endoglin and as a competitor of the fibrinogen-integrin interaction in platelet-dependent thrombus formation. These studies suggest that membrane-bound endoglin and circulating endoglin are important components involved in vascular homeostasis and hemostasis.
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The circulating form of human endoglin (sEng) is a cleavage product of membrane-bound endoglin present on endothelial cells. Because sEng encompasses an RGD motif involved in integrin binding, we hypothesized that sEng would be able to bind integrin αIIbβ3, thereby compromising platelet binding to fibrinogen and thrombus stability.
In vitro human platelet aggregation, thrombus retraction, and secretion-competition assays were performed in the presence of sEng. Surface plasmon resonance (SPR) binding and computational (docking) analyses were carried out to evaluate protein-protein interactions. A transgenic mouse overexpressing human sEng (hsEng⁺) was used to measure bleeding/rebleeding, prothrombin time (PT), blood stream, and embolus formation after FeCl₃-induced injury of the carotid artery.
Under flow conditions, supplementation of human whole blood with sEng led to a smaller thrombus size. sEng inhibited platelet aggregation and thrombus retraction, interfering with fibrinogen binding, but did not affect platelet activation. SPR binding studies demonstrated that the specific interaction between αIIbβ3 and sEng and molecular modeling showed a good fitting between αIIbβ3 and sEng structures involving the endoglin RGD motif, suggesting the possible formation of a highly stable αIIbβ3/sEng. hsEng⁺ mice showed increased bleeding time and number of rebleedings compared to wild-type mice. No differences in PT were denoted between genotypes. After FeCl₃ injury, the number of released emboli in hsEng⁺ mice was higher and the occlusion was slower compared to controls.
Our results demonstrate that sEng interferes with thrombus formation and stabilization, likely via its binding to platelet αIIbβ3, suggesting its involvement in primary hemostasis control.
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This could be because of the continuation of hypertensive medications among these women. It has been reported that serum endoglin increases at early stages of atherogenesis due to damage to endothelial cells [36]. Endoglin expression has been associated with plague neoangiogenesis, collagen production and atherosclerotic lesion stabilization [37].
Preeclampsia (PE) is an important complication of pregnancy that can lead to chronic kidney disease. Soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), the sFlt-1/PlGF ratio and endoglin are biomarkers for the differential diagnosis of PE and other diseases. We aimed to explore the correlation of these biomarkers with long-term renal function, blood pressure and the urine albumin/creatinine ratio (UACR) in PE patients.
34 patients with PE were enrolled. Blood samples for sFlt-1, PlGF, endoglin and the urine albumin/creatinine ratio (UACR) were collected at the time of PE diagnosis (at 35–40 weeks’ gestational age (GA) (87.50% of cases). After delivery, the patients were followed up at three months and one year to assess blood pressure, renal function and the UACR.
Thirty-four PE patients were included, and 17 completed the study. The estimated glomerular filtration rate (eGFR) decreased significantly at three months and one year after follow-up (128.20 ± 10.34 to 120.75 ± 10.166 ml/min/1.73 m² (p = 0.001) at three months and 126.71 ± 9.948 to 114.29 ± 11.274 ml/min/1.73 m² (p < 0.001) at one year). The endoglin level correlated significantly with the eGFR level during PE, but there was no correlation of any biomarker with eGFR, blood pressure, or the UACR at one year.
Women with PE have a reduction of eGFR at three months and one year after the diagnosis of PE. Only endoglin is correlated with eGFR antepartum; however, it is not correlated with long-term renal function, blood pressure or the UACR.
Gestational glucocorticoid exposure disrupts glucose homeostasis that is accompanied by increased endoglin and DPP-4 activity instead of GSK-3 in rats
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Investigators have also suggested that soluble endoglin levels may be used to assess the progression and treatment efficacy of cardiovascular diseases related to endothelial dysfunction (Rathouska et al., 2015). In consonance with our finding that gestational GC exposure led to increase atherogenic dyslipidemia and impaired nitric oxide biosynthesis that is associated with increase endoglin, report exist that endoglin levels increase during the early stages of atherosclerosis due to damaged endothelial cells and then decrease during the later stages of the atherosclerotic process (Li et al., 2000). In another study, the endoglin levels of patients with hypertension and/or type 2 diabetes as well as target-organ damage such as retinopathy, were significantly higher than in the controls (Blázquez-Medela et al., 2010).
Gestational glucocorticoid (GC) treatment has been associated with cardiometabolic disorder (CMD) in offspring’s in later life. Elevated dipeptidyl peptidase-4 (DPP-4) activity, endoglin and glycogen synthase kinase-3 (GSK-3) has also been implicated in the development of insulin resistance (IR) and/or vascular inflammation. We aimed to investigate the impact of GC exposure on glucose metabolism and the circulating levels of inflammatory biomarkers, DPP-4 activity and GSK-3 in pregnant rats. Pregnant Wistar rats received either vehicle or dexamethasone (DEX; 0.2 mg/kg; po) between gestational days 14 and 19. Gestational GC exposure resulted in impaired glucose homeostasis that is accompanied with elevated circulating levels of inflammatory biomarkers (endoglin, uric acid, and platelet/lymphocyte ratio), oxidative stress (malondialdehyde), blood viscosity, reduced NO level and increased DPP-4 activity. However, these effects were associated with atherogenic dyslipidemia and reduced GSK-3.We conclude that plasma endoglin, a marker of vascular inflammation, and plasma DPP-4 activity are increased in pregnant rats treated with GC during late gestation. Therefore, glucose deregulation associated with gestational GC exposure is through endoglin-/DPP-4-dependent but GSK-3-independent pathway.
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Several studies have investigated the relationships between circulating endoglin and atherosclerosis, although the reported results are controversial. Some studies found that higher levels of endoglin are related to hypertension- and diabetes-associated cardiovascular pathological alterations [8], and plaque instability and rupture [9], whereas other studies have indicated that endoglin levels are lower in patients with severe coronary atherosclerosis compared to those with mild atherosclerosis or normal [10,11]. Similarly, studies on the association between the circulating levels of endocan and atherosclerosis have also generated conflicting results.
Accumulating evidence has suggested that endocan and endoglin may play important roles in cardiovascular disease. However, no previous study has focused on these circulating levels in patients with large-artery atherosclerotic (LAA) stroke.
Serum levels of endocan and endoglin in 114 patients with LAA stroke and 114 age- and sex-matched controls were measured by ELISA. Serum samples from patients were available on day 1, day 6 and in the 4th week after ischaemic stroke(IS). Stroke severity was determined based on the NIHSS score and the stroke volume. An unfavourable outcome was defined as a mRS score > 2 on day 90 after IS.
The endocan levels were significantly higher in patients with LAA stroke compared with the controls (p = 0.001), and after adjustment for other factors (p = 0.001). In addition, higher endocan levels were independently associated with unfavourable outcomes on both day 1 and day 6 after IS (p = 0.018 and p = 0.011). Endoglin levels were decreased on day 6 (p = 0.002) and then recovered in the 4th week after IS. No correlation was found between endocan or endoglin and stroke severity.
Endocan levels are higher in patients with LAA stroke and can help in predicting the short-term unfavourable outcome. Endoglin levels are changed after stroke.
Soluble endoglin, hypercholesterolemia and endothelial dysfunction
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In addition, since BMP-9 does not affect eNOS phosphorylation and activation, it was proposed that sEng could not act by preventing this process [2]. On the contrary, we cannot rule out a possibility that sEng was already complexed with sTβRII, thus inhibiting TGF-β1 induced eNOS activity in previous studies [7,12]. In general, the impact of the BMP-9 binding in the vessel pathology remains elusive.
A soluble form of endoglin (sEng) is known to be an extracellular domain of the full-length membrane endoglin, which is elevated during various pathological conditions related to vascular endothelium.
In the current review, we tried to summarize a possible role of soluble endoglin in cardiovascular pathologies, focusing on its relation to endothelial dysfunction and cholesterol levels. We discussed sEng as a proposed biomarker of cardiovascular disease progression, cardiovascular disease treatment and endothelial dysfunction. We also addressed a potential interaction of sEng with TGF-β/eNOS or BMP-9 signaling.
We suggest soluble endoglin levels to be monitored, because they reflect the progression/treatment efficacy of cardiovascular diseases related to endothelial dysfunction and hypercholesterolemia. A possible role of soluble endoglin as an inducer of endothelial dysfunction however remains to be elucidated.

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