elastin and Peripheral-Arterial-Disease

Peripheral arterial disease differentially affects the superficial femoral (SFA) and the popliteal (PA) arteries, but their morphometric, structural, mechanical, and physiologic differences are poorly understood. SFAs and PAs from 125 human subjects (age 13-92, average 52±17 years) were compared in terms of radii, wall thickness, and opening angles. Structure and vascular disease were quantified using histology, mechanical properties were determined with planar biaxial extension, and constitutive modeling was used to calculate the physiologic stress-stretch state, elastic energy, and the circumferential physiologic stiffness. SFAs had larger radii than PAs, and both segments widened with age. Young SFAs were 5% thicker, but in old subjects the PAs were thicker. Circumferential (SFA: 96→193°, PA: 105→139°) and longitudinal (SFA: 139→306°, PA: 133→320°) opening angles increased with age in both segments. PAs were more diseased than SFAs and had 11% thicker intima. With age, intimal thickness increased 8.5-fold, but medial thickness remained unchanged (620μm) in both arteries. SFAs had 30% more elastin than the PAs, and its density decreased ~50% with age. SFAs were more compliant than PAs circumferentially, but there was no difference longitudinally. Physiologic circumferential stress and stiffness were 21% and 11% higher in the SFA than in the PA across all ages. The stored elastic energy decreased with age (SFA: 1.4→0.4kPa, PA: 2.5→0.3kPa). While the SFA and PA demonstrate appreciable differences, most of them are due to vascular disease. When pathology is the same, so are the mechanical properties, but not the physiologic characteristics that remain distinct due to geometrical differences.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Elastin; Femoral Artery; Femur; Humans; Middle Aged; Peripheral Arterial Disease; Popliteal Artery; Stress, Mechanical; Young Adult

High-performance athletes can develop symptomatic arterial flow restriction during exercise caused by endofibrosis. The pathogenesis is poorly understood; however, coagulation enzymes, such as tissue factor (TF) and coagulation factor Xa, might contribute to the fibrotic process, which is mainly regulated through activation of protease-activated receptors (PARs). Therefore, the aim of this explorative study was to evaluate the presence of coagulation factors and PARs in endofibrotic tissue, which might be indicative of their potential role in the natural development of endofibrosis.. External iliac arterial specimens with endofibrosis (n = 19) were collected during surgical interventions. As control, arterial segments of the external iliac artery (n = 20) were collected post mortem from individuals with no medical history of cardiovascular disease who donated their body to medical science. Arteries were paraffinized and cut in tissue sections for immunohistochemical analysis. Positive staining within lesions was determined with ImageJ software (National Institutes of Health, Bethesda, Md).. Endofibrotic segments contained a neointima, causing intraluminal stenosis, which was highly positive for collagen (+150%; P < .01) and elastin (+148%; P < .01) in comparison with controls. Intriguingly, endofibrosis was not limited to the intima because collagen (+213%) and elastin (+215%) were also significantly elevated in the media layer of endofibrotic segments. These findings were accompanied by significantly increased α-smooth muscle actin-positive cells, morphologically compatible with the presence of myofibroblasts. In addition, PAR1 and PAR4 and the membrane receptor TF were increased as well as coagulation factor X.. We showed that myofibroblasts and the accompanying collagen and elastin synthesis might be key factors in the development of endofibrosis. The special association with increased presence of PARs, factor X, and TF suggests that protease-mediated cell signaling could be a contributing component in the mechanisms leading to endofibrosis.

Topics: Adult; Aged; Aged, 80 and over; Athletes; Athletic Performance; Cadaver; Case-Control Studies; Collagen; Constriction, Pathologic; Elastin; Factor X; Female; Fibrosis; Humans; Iliac Artery; Male; Middle Aged; Myofibroblasts; Peripheral Arterial Disease; Receptor, PAR-1; Receptors, Thrombin; Thromboplastin; Up-Regulation; Vascular Remodeling; Young Adult

Femoropopliteal artery (FPA) mechanics play a paramount role in pathophysiology and the artery's response to therapeutic interventions, but data on FPA mechanical properties are scarce. Our goal was to characterize human FPAs over a wide population to derive a constitutive description of FPA aging to be used for computational modeling. Fresh human FPA specimens ([Formula: see text]) were obtained from [Formula: see text] predominantly male (80 %) donors 54±15 years old (range 13-82 years). Morphometric characteristics including radius, wall thickness, opening angle, and longitudinal pre-stretch were recorded. Arteries were subjected to multi-ratio planar biaxial extension to determine constitutive parameters for an invariant-based model accounting for the passive contributions of ground substance, elastin, collagen, and smooth muscle. Nonparametric bootstrapping was used to determine unique sets of material parameters that were used to derive age-group-specific characteristics. Physiologic stress-stretch state was calculated to capture changes with aging. Morphometric and constitutive parameters were derived for seven age groups. Vessel radius, wall thickness, and circumferential opening angle increased with aging, while longitudinal pre-stretch decreased ([Formula: see text]). Age-group-specific constitutive parameters portrayed orthotropic FPA stiffening, especially in the longitudinal direction. Structural changes in artery wall elastin were associated with reduction of physiologic longitudinal and circumferential stretches and stresses with age. These data and the constitutive description of FPA aging shed new light on our understanding of peripheral arterial disease pathophysiology and arterial aging. Application of this knowledge might improve patient selection for specific treatment modalities in personalized, precision medicine algorithms and could assist in device development for treatment of peripheral artery disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Arteries; Biomechanical Phenomena; Collagen; Elastin; Female; Humans; Male; Middle Aged; Models, Biological; Peripheral Arterial Disease; Young Adult

This study was designed to determine whether vonapanitase (formerly PRT-201), a recombinant human elastase, treatment can fragment the protein elastin in elastic fibers and cause dilation of atherosclerotic human peripheral arteries subjected to ex vivo balloon angioplasty.. Seven patients undergoing lower limb amputation for peripheral artery disease or who died and donated their bodies to science donated 11 tibial arteries (5 anterior, 6 posterior) for this study. All arteries were atherosclerotic by visual inspection. The arteries underwent ex vivo balloon angioplasty and thereafter were cut into rings and studied on wire myographs where the rings were stretched and tension was recorded. After treatment with vonapanitase 2 mg/mL or vehicle control, myography was repeated and the rings were then subject to elastin content measurement using a desmosine radioimmunoassay and elastic fiber visualization by histology. The wire myography data were used to derive compliance, stress-strain, and incremental elastic modulus curves.. Vonapanitase treatment reduced elastin (desmosine) content by 60% and decreased elastic fiber histologic staining. Vonapanitase-treated rings experienced less tension at any level of stretch and as a result had shifts in the compliance and stress-strain curves relative to vehicle-treated rings. Vonapanitase treatment did not alter the incremental elastic modulus curve.. Vonapanitase treatment of atherosclerotic human peripheral arteries after ex vivo balloon angioplasty fragmented elastin in elastic fibers, decreased tension in the rings at any level of stretch, and altered the compliance and stress-strain curves in a manner predicting arterial dilation in vivo. Based on this result, local treatment of balloon angioplasty sites may increase blood vessel diameter and thereby improve the success of balloon angioplasty in peripheral artery disease.

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon; Atherosclerosis; Carrier Proteins; Elastic Modulus; Elastic Tissue; Elastin; Female; Humans; Male; Middle Aged; Myography; Pancreatic Elastase; Peripheral Arterial Disease; Tibial Arteries; Vasodilation

At physiologic pressures, elastic fibers constrain artery diameter. Local treatment of atherosclerotic arteries with PRT-201, a recombinant type I elastase, could result in fragmentation and removal of elastin fibers and increased vessel diameter.. To investigate the use of PRT-201 as a treatment for human atherosclerotic arteries.. Arteries were harvested from donor legs amputated due to severe peripheral artery disease or from recently deceased persons who donated their bodies to science. Three- to four-centimeter artery segments were studied on a perfusion myograph to obtain baseline diameter data. After treatment with PRT-201 3.6 mg/mL or saline for 30 minutes myography was repeated. PRT-201 treatment resulted in an increase in vessel diameter across a range of transmural pressures. Average anterior tibial artery diameter increased by 0.78 ± 0.21 mm (27% ± 12%), whereas average posterior tibial artery diameter increased by 0.58 ± 0.30 mm (21% ± 11%), both P < 0.001. Elastin content as measured by desmosine radioimmunoassay was reduced by approximately 50%, P < 0.001.. The results suggest that PRT-201 treatment of atherosclerotic peripheral arteries in patients could increase artery diameter, and thus luminal area, possibly alleviating some of the symptoms of peripheral artery disease.

Topics: Aged; Aged, 80 and over; Atherosclerosis; Carrier Proteins; Elastic Tissue; Elastin; Female; Humans; Male; Middle Aged; Myography; Pancreatic Elastase; Peripheral Arterial Disease; Pilot Projects; Recombinant Proteins; Tibial Arteries