Vasa vasorum in plaque angiogenesis, metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy: a malignant transformation

Abstract

Background: Vascularization is an exciting and complex mechanism involving angiogenesis and arteriogenesis. The metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) are associated with multiple metabolic toxicities, which result in reactive oxygen species (ROS) due to an elevated tension of oxidative-redox stress and an accelerated atherosclerosis termed atheroscleropathy.

Results: This atheroscleropathy is associated with accelerated angiogenesis within the vulnerable, thin-cap fibro-atheroma, prone to rupture resulting in acute coronary syndromes (ACS). The resulting intimopathy with its neovascularization due to angiogenesis of the adventitial vasa vasorum (Vv) is prone to intraplaque hemorrhage (IPH). These IPH are associated with destabilization of the vulnerable plaques resulting in plaque erosion and plaque rupture resulting in ACS. In atheroscleropathy the adventitial Vv invades the plaque in a malignant-like fashion and concurrently is associated with chronic inflammation, as macrophages are being deposited within the shoulder regions of these vulnerable plaques. These angiogenic Vv provide a custom delivery vascular network for multiple detrimental substrates, which further accelerates the growth of these vulnerable plaques and atheroscleropathy. There exists a vascularization paradox in MS and T2DM, in that, angiogenesis within the plaque is induced and arteriogenesis is impaired.

Conclusion: This review will attempt to provide a database of knowledge regarding the vascularization process (angiogenesis and arteriogenesis) and its mechanisms to better understand the increased cardiovascular risk and the increased morbidity and mortality associated with MS and T2DM.

Figure 1

The important role of the metabolic syndrome in the development of coronary heart disease. The metabolic syndrome consists of multiple clinical syndromes and metabolic abnormalities, which accelerates the atherosclerotic process. The NCEP ATP III guidelines allows for an easier identifications of these patients at risk. While insulin resistance is central to the development of coronary heart disease, it can be seen that each of the components now contained within the metabolic syndrome can individually contribute to CHD risk. Each of these factors is combined as in the metabolic syndrome they become synergistic.

Figure 2

The atheroscleropathy associated with MS, PD, and T2DM has many deleterious pathways. There are multiple deleterious pathways associated with MS, PD, and T2DM. Atheroscleropathy is pro oxidative-redox stress, prothrombotic, pro-fibrotic, and pro-inflammatory. Each of these mechanisms and the disease process of atheroscleropathy promote a pro-angiogenic environment and associated with a diabetic vascularization paradox, in that, plaque angiogenesis is induced and arteriogenesis is impaired.

Figure 3

Vulnerability of the thin cap fibroatheroma. The vulnerable plaque: Currently the vulnerable plaque has been defined as containing the following: 1. Large lipid core. 2. Thin fibrous cap. 3. Inflammatory changes at the shoulder of the fibrous cap. 4. Decreased smooth muscle cells within the fibrous cap. This "Hot" – vulnerable thin-cap fibrous atheromatous plaque is associated with angiogenesis, inflammation, being lipid laden and acidic, and fibrotic. The endothelium is activated and these plaques are prone to rupture resulting in acute coronary syndromes.

Figure 4

Plaque angiogenesis induced in MS, PD, and T2DM. Angiogenesis within the unstable atherosclerotic plaque: In health the vasa vasorum usually has a single vessel that runs parallel to each side of the epicardial artery being nourished with occasional interconnecting conduits from one side of the artery to the other. In this image, the native parallel adventitial vasa vasorum (in black) can be differentiated from the red neovascularization of the intima and media. The unstable, vulnerable plaques are associated with a malignant like invasion of the intima-media by adventitial derived vasa vasorum fragile vessels, which are prone to rupture resulting in intraplaque hemorrhage. These intraplaque hemorrhages accelerate plaque vulnerability and are associated with plaque rupture and acute coronary events.

Figure 5

The 10 point process of angiogenesis visulized. The 10 point process of angiogenesis: Intraplaque hemorrhage (IPH) may serve as an angiogenic stimulus for the further development of excessive vasa vasorum invasion of the intima and media, resulting in an even more unstable vulnerable plaque: prone to rupture. As the MMPs drill the openings for the invading adventitial Vv they may also contribute to the disruption of the internal elastic lamina, which contributes to the plaques instability. Additionally, the extravasated RBC plasma membranes become incorporated into the necrotic core and contribute to the enlargement of the necrotic core, as well as, providing an antigenic stimulus for the continued intraplaque inflammatory response.

Figure 6

The spirit of vascularization. This figure compares and contrasts the involved mechanisms of angiogenesis and arteriogenesis. S = substrates, P = promotors, I = inducers, R = results, I = the common role of inflammation, and T = time. This acronym helps to understand why angiogenesis is induced and arteriogenesis is impaired.

Figure 7

Impairment of remodeling collateralization due to PAI-1. PAI-1 elevations impair fibrinolysis and contribute to a prothrombotic state in MS, PD, and T2DM. Additionally PAI-1 elevations impair Arteriogenesis. Remodeling collateralization is impaired in MS, PD, and T2DM due to elevations in PAI-1. Conversion of plasminogen to plasmin by tPA – uPA is negatively effected by elevations in PAI-1. This defect in the generation of Plasmin results in decreased conversion of latent MMPs to active MMPs and impair the remodeling necessary for the required remodeling of the preexisting arterioles to larger arterioles necessary for a more functional blood flow around obstructed epicardial coronary arteries and obstructed peripheral vascular systems in MS, PD, and T2DM.