The central role of vascular extracellular matrix and basement membrane remodeling in metabolic syndrome and type 2 diabetes: the matrix preloaded

Abstract

The vascular endothelial basement membrane and extra cellular matrix is a compilation of different macromolecules organized by physical entanglements, opposing ionic charges, chemical covalent bonding, and cross-linking into a biomechanically active polymer. These matrices provide a gel-like form and scaffolding structure with regional tensile strength provided by collagens, elasticity by elastins, adhesiveness by structural glycoproteins, compressibility by proteoglycans--hyaluronans, and communicability by a family of integrins, which exchanges information between cells and between cells and the extracellular matrix of vascular tissues. Each component of the extracellular matrix and specifically the capillary basement membrane possesses unique structural properties and interactions with one another, which determine the separate and combined roles in the multiple diabetic complications or diabetic opathies. Metabolic syndrome, prediabetes, type 2 diabetes mellitus, and their parallel companion (atheroscleropathy) are associated with multiple metabolic toxicities and chronic injurious stimuli. The adaptable quality of a matrix or form genetically preloaded with the necessary information to communicate and respond to an ever-changing environment, which supports the interstitium, capillary and arterial vessel wall is individually examined.

Figure 1

multiple injurious stimuli to the Endothelium, intima, media, and adventitia. The endothelial cell is exposed to multiple injurious stimuli consisting of: modified LDL-cholesterol, various infection insults (viral and bacterial), angiotensin II, hemodynamic stress, LPa, glucose, homocysteine, uric acid, Ca++, phosphorus, parathyroid hormone, and intimal redox stress or reactive oxygen species. These multiple injurious stimuli (A-FLIGHT-U) cause a chronic injury and a response to injury with resultant remodeling of the arterial vessel wall and in particular the ECM. In the MetS, prediabetes, and overt T2DM, these stimuli act in concert to result in this detrimental remodeling with structural-functional abnormalities and dysfunction. The endothelium and its BM act as the first line of defense and are therefore the first cell and matrix to be affected with resulting dysfunction and structural changes. MetS, prediabetes, and T2DM undergo an accelerated atherosclerosis we term atheroscleropathy. Oxidation, glycation, glycoxidation, or homocysteinylation must modify LDL-cholesterol for LDL-C to become atherogenic. Multiple injurious stimuli acting alone and synergistically to modify LDL-cholesterol with resultant matrix structural defects accelerating atherogenesis and angiogenesis are observed. Each layer of the arterial vessel wall is eventually affected by these injurious stimuli initially from the lumen outward (inside-out) and later in the process to effect the plaque vulnerability from the outside-in (adventitial layer) by an inducible set of custom delivery vessels called the vasa vasorum.

Figure 2

The basement membrane exploaded. This image expands – explodes the BM and demonstrates the importance of each of its components that are involved in the expansion and thickening of the BM in MetS, prediabetes, and T2DM. The BM is an integral part of the ECM and plays such an integrating role in the structural – functional changes associated with MetS, prediabetes, and T2DM. An integrin has been placed in this image to verify its important-integrating role in cell-cell, cell-matrix communication. This image demonstrates the existence of a shape and a form to the PAS+, hyaline staining, thickened BM in MetS, prediabetes, and T2DM.

Figure 3

The integrins. This image portrays the integrin family of transmembrane molecules (receptors), which interact with the molecules of the ECM (ligands) and ligands associated with other cellular elements. Integrins are heterodimers, consisting of an alpha unit on the left made up of two disulfide bonded polypeptide chains. The beta unit on the right consists of a single polypeptide chain. Integrins bind to matrix ligand binding sties, which are specific amino acid sequences (usually 3–8) and at the top of this image the RGD (arginine, glycine, and aspartyl amino acids) matrix ligand – binding site is demonstrated. There are three domains: the extracellular domain – the transmembrane domain – the cytosolic domain, which interact with the cytosolic cytoskeletal proteins: Actin and Talin. These special transmembrane molecules allow for the "outside in" and "inside out" communication between cells and the ECM. Glucotoxicity affects integrin function through decreased perlecan within BMs and this may increase the susceptibility of endothelial cell dysfunction and demise (apoptosis), allowing for endothelial cell erosion and loss of endothelial cell stability upon its BM increasing the possibility of plaque erosion – rupture and thrombosis.

Figure 4

Formation of age. The formation of AGE, as a result of chronic hyperglycemia, is complex and this figure demonstrates the steps and time frames involved in the formation of AGE and cross-linking of proteins. This complex process is reversible until the NH-R⁽ⁿ⁾ 's are crosslinked.

Figure 5

The metabolic syndrome "Reloaded". MetS (Syndrome X) "reloaded" is a unique clustering of clinical syndromes and metabolic derangements. Reaven initially described the MetS in 1988. He initially discussed the four major determinants consisting of: I. Hypertension. II. Hyperinsulinemia. III. Hyperlipidemia (Dyslipidemia of elevated VLDL – triglycerides, decreased HDL-cholesterol, and elevated small dense atherogenic LDL-cholesterol). IV. Hyperglycemia or impaired glucose tolerance, impaired fasting glucose, or even overt T2DM and the central importance of insulin resistance and hyperinsulinemia. The important association of polycystic ovary syndrome (PCOS), hyperuricemia, fibrinogen, hsCRP, microalbuminuria, PAI-1, and more recently reactive oxygen species (ROS), NASH, and the damaging oxidative potential of Hcy and endothelial dysfunction have all contributed to a better understanding of this complicated clustering phenomenon. ROS, and those with a white background: Hyperuricemia, microalbuminuria, hyperhomocysteinemia, highly sensitive CRP, indicate the newer additions giving rise to the new terminology: Metabolic Syndrome Reloaded.

Figure 6

Renal glomerular Remodeling. This image portrays a normal nephron unit on the left transitioning to an abnormal remodeled nephron unit with changes representative of diabetic nephropathy and changes of glomerulosclerosis. Left: Normal renal capillary glomerular and tubulo-interstitial structures. Transitioning to the Center of the image is the mesangial stalk with mesangial cell hyperplasia (yellow) and mesangial expansion with loss of foot processes of the podocyte (also termed visceral epithelium) (blue) and increasing thickness of the glomerular BM (red). Right: Increased capillary glomerular BM thickening (red) with atrophic podocytes and loss of foot processes of the podocyte (blue) to the capillary glomerular endothelial cell. Right: Also depicts tubulo-interstitial fibrosis with expansion of the peritubular (blue) extracellular matrix (fibrosis) with an increased thickening of the tubular BM (red). Just below the efferent (blue) arteriole is depicted hyaline arteriolosclerosis and just above the afferent arteriole (red) is depicted hyperplastic arteriolosclerosis with its characteristic "onion skin" like changes. The thickened BMs, arteriolar changes, and the mesangial expansion all are PAS+, hyaline staining, and contain large amounts of type IV collagen with increased laminin and fibronectin with concurrent decreased amounts of heparin sulfate proteoglycan (perlecan). Continuous with the proximal tubules (green) is the outer parietal epithelial cells (green), which constitutes the outer structure of Bowman's capsule and Bowman's space.

Figure 7

Pkc activation. This figure demonstrates the multiple deleterious actions and mechanisms of PKC beta II isoform on cellular function and ECM remodeling and BM thickening.