On Collateral Development In Diabetes Mellitus Dm Angiogenesis And Collateral Growth

Angiogenesis in its broader sense describes the growth of new blood vessels, which is a compensatory process in response to either the limitation or cessation of regional blood supply secondary to advanced atherosclerotic disease. Angiogenesis can be observed in various vascular beds leading to coronary artery disease (CAD), peripheral artery disease (PAD), or can be the response to local inflammation as observed in wound healing. Angiogenesis in its broader sense comprises two independently occurring mechanisms: i.) angiogenesis in its narrow sense, i.e. the growth of new capillaries, which is predominantly driven by regional ischemia and inflammation, which is also observed in wound healing; and ii.) arteriogenesis, i.e. the growth of (preformed) collateral vessels, which is driven by the redirection of blood flow resulting in enhanced shear stress as an initial trigger for collateral artery growth.

Endothelial cells (EC) initiate an angiogenic process consisting of the induction of microvascular hyperpermeability, local degradation of the basement membrane, EC proliferation migration and sprouting into the local stroma, reconstruction of basement membrane, maturation of new blood vessel, and stabilization by recruiting pericytes [1]. At the initial step, the proper balance of vasodilation and vasoconstriction appears to be important to allow adequate exsudation of plasma proteins, which in turn serve as primary scaffolds for the vascular wall cells to allow growth and expansion (proliferation and migration).

EC are the most important cell type in the process of new vessel growth as they can initiate angiogenesis. In addition, periendothelial cells are essential for the process to complete and for the newly formed vessels to mature. Mural cells, namely vascular smooth muscle cells (VSMC), fibroblasts and pericytes stabilize immature vessels by inhibiting EC proliferation and migration, and by stimulating production of extracellular matrix (ECM) [1]. They thereby provide hemostatic control and protect new endothelium-lined vessels against rupture or regression.

Arteriogenesis describes the process of enlargement of preexisting collateral vessels. During the process of arteriogenesis, the arteriolar media enlarges by the growth of the SMC layer, which results in vessels with full vasomotor properties, so that they can functionally adapt to changes in tissue perfusion. Periendothelial cells modulate EC in acquiring specialized functions in different vascular beds [2].

The process of capillary sprouting during angiogenesis has been studied in detail: To emigrate from the "mother" vessel, EC need to loosen interendothelial cell contacts and contacts with periendothelial cells; i.e. the mother vessel becomes destabilized. Hereby, angiopoietin-2 (Ang2), an inhibitor of Tie2 signaling, appears to be involved in detaching SMC and loosening the matrix [3]. Enzymes belonging to the families of plasminogen activator, matrix metalloproteinase (MMP), chymase or heparanase play a critical role in angiogenesis by degrading ECM molecules and by activating/liberating growth factors (GFs) such as basic fibroblast GF (bFGF), vascular endothelial GF (VEGF) and insulin-like GF-1 (IGF-1), sequestered within ECM [4].

Angiogenesis is strictly regulated by signals from the serum and from the surrounding ECM environment [1]. Angiogenesis is a complex event that is highly dependent on diverse soluble factors acting in a consecutive, concerted, or synergistic manner. These angiogenic factors act on "angiogenic" cells, i.e. EC, VSMC, fibroblasts as well as circulating cells such as monocytes, lymphocytes and circulating progenitor cells (CPC). VEGF [5], Ang [6], FGF [7] and transforming GF-( (TGF-() [8] are growth factors most critical for angiogenesis. Growth factors act upon angiogenic cells thereby reprogramming basic physiological processes and turning the cells into an angiogenic phenotype [1]. Specific cellular aspects are proliferation, differentiation, apoptosis and survival, adhesion and migration.

1.1. Diabetes Mellitus and Vascular Pathology

Diabetes mellitus (DM) is associated with an increased incidence of morbidity and mortality from atherosclerotic disease including CAD and PAD [9, 10]. The pathogenic influence of DM on the development and prognosis of CAD is well established. The risk of myocardial infarction (MI) increases and appears to be associated with hyperglycemia [11, 12]. The risk for the development of microvascular disease, however, was thought to occur only with more extreme hyperglycemia [13]. Furthermore, increased mortality following MI and stroke is associated with hyperglycemia and increased levels of glycosylated HbA1c correlated with higher incidence of another fatal MI and stroke [14]. Importantly, no clear threshold can be provided for the risk of developing macrovascular complications in DM [15]. The same study, the United Kingdom prospective diabetes study (UKPDS) has clearly shown that the incidence of cardiac and peripheral macrovas-cular complications of DM tremendously increases with increasing concentrations of HbA1c. Increase in the levels of HbA1c by 1% above normal value results in an approximately 50% increase in the rate of fatal and non-fatal MIs, 30% increase in fatal or non-fatal strokes and about 150% increase in amputation or death from peripheral vascular disease (PVD) [15]. The increase in mortality from PVD results from the complex and severe complications of PVD including ischemia, infections and neuropathy [16, 17]. On the contrary, intensive glycemic control results in a significant improvement of the frequency of cardiac and peripheral macrovascular complications of DM [15]. The decrease in HbA1c levels by 1% leads to a 14% decrease in the risk of MI, to a decreased risk of stroke by 12% and to a 43% decreased risk in amputation and fatal PVD [15]. Resent metaanalysis of randomized controlled trials suggests that attempts to improve glycemic control reduce the incidence of macrovascular events both in type 1 and type 2 DM [18].

Compared with age-matched individuals, diabetic patients often present with more widespread atherosclerotic disease, more severe lesions and a larger number of vascular occlusions [19-21]. DM is associated with endothelial dysfunction and thereby contributes to the development and progression of atherosclerotic diseases [22]. It is important to note that endothelial dysfunction can already be detected in young patients with early signs of insulin resistance independent of other classic cardiovascular risk factors [23].

The higher severity of CAD and PAD in diabetic patients has been linked to an impaired ability to develop an adequate collateral circulation, i.e. impaired arterio-genesis [24, 25]. The possibility to assess the mechanisms of impaired arteriogenesis in patients has been limited to i.) the descriptive imaging of collateral vessels using conventional angiography or magnetic resonance imaging-based angiography, and ii.) the invasive assessment of collateral blood flow and collateral resistance based on temporary coronary artery occlusion (or in chronic total coronary occlusions) and collateral pressure and flow measurements [26, 27]. These clinical findings are in accordance with morphometric and histological studies on autopsied hearts [28, 29] (see 1.2). These pathomorphological studies were able to provide some insight into the intrinsic mechanisms behind the impaired arteriogenesis in DM. The studies on collateral circulation are summarized in Table 1.

Recently, independent functional data on the impaired collateral circulation in diabetic individuals came from the functional analysis of circulating cells that contribute to arteriogenesis, namely monocytes, lymphocytes and circulating progenitor cells (CPC). The functional response of monocytes is impaired in diabetic individuals as demonstrated by ex vivo analysis [25, 30]. Monocytes from diabetic individuals cannot migrate towards VEGF-A, a relevant arteriogenic stimulus [31, 32], while they still can migrate towards the tripeptide formyl-Met-Leu-Phe (fMLP) [30]. The functional defect in these monocytes is based on an intracellular signal transduction defect as the kinase function of the relevant cell surface receptor, i.e. VEGF receptor-1 (VEGFR-1) was fully intact. The functional defects observed in the circulating monocytes appear to mirror the status of other vascular cells involved in arteriogenesis. As these cells allow the detection of pathology-related cellular and vascular defects, they can be used to detect negative influences on the vasculature (concept of a "biosensor"). The analysis of the effect of DM on resident "angiogenic" cells, namely EC and perivascular cells (SMC and fibroblasts) is rather limited due to the lack of possibilities to isolate them and to study them ex vivo. So far, only fibroblasts could be isolated from patients and studied in relation to DM and wound healing [33], the latter being strictly dependent on angiogenesis.

Most of our understanding of DM-related mechanisms of impaired angiogenesis and arteriogenesis arises from animal models of DM and in vitro cellular models studying the effect of different pathophysiological mechanisms of DM. These studies could provide us with the understanding of intracellular biochemical aberrations resulting in: i.) defects in the production and expression of crucial angiogenic factors and their receptors; ii.) aberrant production and maturation of ECM components, and iii.) dysfunction of the cells contributing to vascular growth. All this

Table 1. Clinical studies on the coronary collateral circulation in humans with diabetes mellitus

Author, year [ref]

Nr. of

Method of assessment of coronary

Specific findings in the diabetic patients and/or tissue samples

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