Background

In the human heart, vascular channels with lumen diameter ranging from 40 to 200 μm link large conductance coronary arteries to one another. These interconnecting arteriolar networks are called coronary collaterals [1, 2]. Abundant evidence indicates that when the proximal part of a major epicardial coronary artery is transiently or permanently occluded, the development of coronary collateral circulation serves as a natural conduit system bridging the occluded coronary vessels [3, 4]. Although these anastomoses are often incapable of restoring flow to normal levels, well-developed coronary collaterals could, at least partially, supplies the downstream perfusion area via the arteriolar connection (Fig. 1), thereby preventing or alleviating myocardial ischemia, reducing infarct size, protecting left ventricular function, and even decreasing mortality [5, 6].

Fig. 1
figure 1

Coronary angiogram of a 58-year-old patient with stable angina. Upper: total occlusion of proximal left anterior descending artery; bottom: well-formed collaterals (Rentrop grade 3) supplied by the right coronary artery

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Epidemiological data frequently demonstrate that type 2 diabetes mellitus (T2DM) is increasingly prevalent and represents an important risk factor for cardiovascular disease involving arteries and/or capillaries [7]. Compared with non-diabetic patients, those with T2DM often have more severe and diffuse coronary atherosclerosis, more complicated revascularization procedures (percutaneous coronary intervention [PCI] or coronary bypass grafting surgery), and less favorable long-term outcomes (e.g., higher rates of in-stent restenosis, stent thrombosis, and coronary atherosclerotic disease progression) [8]. In fact, cardiovascular disease remains the major cause of death for almost three quarters of type 2 diabetic patients, in which impaired coronary collateral formation may play a role [9].

In this review, we will describe the effects of T2DM on collateral vessel growth and discuss the role of clinical and biochemical factors as possible markers of reduced coronary collateralization and their clinical relevance in type 2 diabetic patients with stable coronary artery disease and chronic total occlusion (CTO), with the reference to the recent researches.

Potential mechanisms of impaired collateral growth in diabetes

In adult organisms, the compensatory growth of blood vessels under ischemic conditions is an appreciated response, which can be achieved in two distinctive ways (i.e., arteriogenesis and angiogenesis) [10]. The process of arteriogenesis is stimulated by physical force and accompanied with enlargement and maturation of pre-existing arterioles (i.e., arterialization of the capillary bed). Briefly, when a coronary artery becomes completely occluded, the pressure gradient across the collaterals is elevated, which results in an increase in blood flow velocity and tangential fluid shear stress imposed on the endothelium, leading to a series of cellular response, including modulation of cell adhesion molecules that would in turn facilitate adhesion and transmigration of circulating mononuclear cells to sites of arterial formation. These cells then become activated and secrete matrix-degrading proteinases, leading to outward arterial remodeling. They also release other cytokines that contribute to the growth of arteriolar collaterals. Recent studies have shown that many genes related to inflammation, transcription, and neovascularization are significantly upregulated in the ischemic regions and associated with collateral growth [11]. The oxygen gradient over the collateral vessels is increased in patients with a less matured collateral circulation and related to local levels of pro-arteriogenic cytokines [12, 13]. Angiogenesis, sprouting of new capillaries from the pre-existing vessels, is induced by hypoxia-inducible factor 1-α and driven largely by vascular endothelial growth factor (VEGF) released either by ischemic tissues or by inflammatory cells. Angiogenesis is entirely regulated by a balance of pro- and anti-angiogenic factors [3]. Although formation and maturation of blood vessels are dependent on endothelial and vascular smooth muscle cells, and affected by various growth factors and inflammatory cytokines, the increase in diameter via arteriogenesis weights much more than the number of newly formed capillaries via angiogenesis [1,2,3].

The mechanism of reduced coronary collateralization in T2DM remains unclear and is likely multifactorial. Although the presence of a chronic coronary total occlusion would be expected to significantly decrease intracoronary pressure distal to the occluded segment which could promote arteriogenesis, there exists a trend towards severe coronary atherosclerosis in type 2 diabetic patients as manifested by long and diffuse lesions and small vessel disease, which could reduce pressure gradient between the collateral donor artery and collateral recipient one, and therefore, limits collateral vessel growth and function. The PROSPECT study with gray-scale and radiofrequency intravascular ultrasound showed that type 2 diabetic patients often have coronary atherosclerotic lesions characterized by a large necrotic core, thin-cap fibroatheroma, and high calcium content, especially for those with a longer duration of T2DM and poorer glycemic control [14]. These coronary lesion characteristics favor plaque instability and degradation, and predict future major adverse cardiac events independent of myocardial ischemia [15]. Previous studies have revealed that glucose fluctuations provoke oxidative stress that leads to endothelial cell dysfunction, progression of coronary atherosclerosis, and plaque vulnerability [16, 17]. These results suggest that there may be a symbiotic relationship between vulnerable plaque and T2DM. Recently, Hinkel et al. reported that diabetic human myocardial explants revealed capillary rarefaction and pericyte loss compared to nondiabetic explants. Moreover, they found that in a diabetic pig model, hyperglycemia induced microvascular rarefaction in the myocardium even without ischemia, and capillary density further decreased in chronic ischemia hearts [18]. These observations highlight that T2DM destabilized microvascular vessels of the heart and may impair the responsiveness of ischemic myocardium to proangiogenic factors. Data from prior studies have also shown a pronounced increase of collateral resistance, adverse functional and structural remodeling of the coronary arterioles, and obliteration of pre-existing blood vessels in T2DM [19,20,21]. All these changes jointly lead to reduced arteriogenic property in type 2 diabetic patients.

Chronic hyperglycemia and altered redox state in diabetes increase the formation and accumulation of advanced glycation endproducts (AGEs). Binding of AGEs to receptor for AGEs (RAGE) activates several intracellular signaling pathways including activation of mitogen activated protein kinase (MAPK), p21ras and NF-κB translocation, resulting in enhanced oxidative stress and upregulation of many inflammatory genes [22]. Furthermore, overexpression of RAGE has negative effects on endothelial function, neointima formation, and angiogenesis [23]. Additionally, in a diabetic setting, pro-angiogenic factors including VEGF, fibroblast growth factor (FGF), and other collateral vessel growth related parameters are altered. There exists endothelial dysfunction characterized by decreased synthesis of nitric oxide, increased expression of endothelin-1 and adhesion molecules, elevated basal oxidative stress or more oxidative redox state, and increased vascular permeability [24]. Impaired monocyte/macrophage recruitment has been shown to be responsible for reduced collateral growth under diabetic conditions [25], and cytokines (e.g., transforming growth factor β, tumor necrosis factor [TNF]-α, monocyte chemotactic protein [MCP]-1, C-reactive protein [CRP], interleukin-8 and interleukin 20) and cell-extracellular matrix interaction may also play a role [24]. It has been shown that downstream VEGF receptors (VEGFRs) and Rho/Rho kinase pathway are important in the regulation of collateral development. Soluble VEGFR-1 is a negative endogenous modulator of angiogenesis by binding and sequestering VEGF. Increased expression and secretion of soluble VEGFR-1 prevents in vivo and in vitro capillary growth and angiogenesis [26]. The expression of soluble VEGFR-1 is decreased in hypoxia status and this protein molecule is degraded by local matrix metalloproteinase-7 to allow VEGF to escape sequestration in ischemic lesions [27]. In addition, soluble VEGFR-2 exhibits anti-lymphangiogenic property and its serum levels are related to insulin resistance in patients with metabolic syndrome, whereas the biological effect of soluble VEGFR-3 remains unclear [28]. These results suggest that VEGF-soluble VEGFR-1 mechanism is crucial to physiological homeostasis of vasculature and modulation of pro- and anti-angiogenesis. We have demonstrated elevated serum soluble VEGFR-1 and soluble VEGFR-2 levels and remarkably reduced VEGF and placenta growth factor levels in type 2 diabetic patients with CTO and low coronary collateralization [29], indicating a linkage of this negative regulator of angiogenesis to impaired coronary collateral formation. Previous studies have observed that myocardial expression of VEGFR-2 is reduced along with a down-regulation of its signal transduction in type 2 diabetic patients [30] and that AGEs inhibit VEGFR-1-mediated chemotaxis in diabetic monocytes [31]. Serum soluble VEGFR-1 level is increased in patients with T2DM [32], and diabetic condition aggravates vascular inflammation through amplifying RAGE-mediated mechanism [33]. In patients with T2DM, glycation of apoprotein A attenuates atheroprotective function of high-density lipoprotein (HDL), and, in contrast, glycation of apoprotein B reinforces low-density lipoprotein-induced inflammatory response [34, 35]. Thus, diabetic pathophysiology promotes an anti-angiogenic process and meanwhile mitigates pro-angiogenic factors in coronary vasculature during ischemia, jointly leading to impaired collateral growth.

Metabolic syndrome characterized by a cluster of risk components including abdominal obesity, insulin resistance, hyperglycemia, dyslipidemia and hypertension has been considered as one of the significant factors affecting adversely the development of coronary collateral vessels. In fact, this syndrome remained an independent risk factor for poor coronary collateralization even after adjusting for T2DM, and approximately 30–40% of these patients show little to no coronary collateral growth [36]. Previous studies indicated that an increasing number of component pathologies of the metabolic syndrome correlated with increasingly poorer coronary collateral development by angiographic grading systems [24]. Metabolic syndrome compromises vascular adaptations to ischemia, resulting in impaired coronary collateral growth. Central to this inadequate adjustment is impairment in endothelial function produced by oxidative stress, which also corrupts the signal transduction of growth factors [36].

Factors influencing coronary collateralization in diabetes

Besides severity of coronary obstruction [37, 38], numerous factors that could possibly attenuate the development and biological function of coronary collaterals have been reported such as old age [39], traditional risk factors for coronary artery disease [40,41,42,43,44], hyperlipoprotein (a) [89]. Emerging evidence suggests that microRNAs are implicated in a variety of physiological processes, including glucose homeostasis [90]. Circulating microRNAs in the plasma of patients with stable coronary artery disease and CTO may provide information about the coronary collateral capacity. For example, elevated miR-320 and miR-221 levels were indicative of endothelial dysfunction and accompanied with impaired angiogenesis in diabetes, whereas microRNA-126 was increased in patients with well-developed collateral circulation, along with VEGF levels [91]. In addition, although serum HDL was associated with the development of coronary collateral circulation [92], coronary atherosclerosis is more influenced by HDL quality than by its quantity in the diabetic condition. Glycation of apolipoprotein A-I and A-IV has been shown to be related to the presence and severity of coronary artery disease and plaque progression in T2DM [93,94,95]. Their effects on coronary collateral vessel growth in T2DM are currently investigated.

Conclusions

T2DM adversely affects coronary collateral development through multiple cellular mechanisms on arteriogenesis and angiogenesis, and the formation of coronary collaterals in patients with T2DM and CTO is influenced by various clinical, biochemical and angiographic factors. Therefore, studies on the relationship between T2DM and coronary collateral circulation are clinically relevant in terms of understanding coronary pathophysiology in diabetes and searching for potential new therapeutic target in future.