New insights into mechanisms whereby the extracellular matrix takes part in the control of smooth muscle cell proliferation suggest a number of putative targets for future therapies that can be applied to increase plaque stability, prevent the clinical consequences of atherosclerosis and improve outcomes after interventional procedures and organ transplantation.

The growth of neointima and neointimal smooth muscle cells in baboon polytetrafluoroethylene grafts is regulated by blood flow. Because neointimal smooth muscle cells express both platelet-derived growth factor receptor-alpha and -beta (PDGFR-alpha and -beta), we designed this study to test the hypothesis that inhibiting either PDGFR-alpha or PDGFR-beta with a specific mouse/human chimeric antibody will modulate flow-induced neointimal formation. Bilateral aortoiliac grafts and distal femoral arteriovenous fistulae were placed in 17 baboons. After 8 weeks, 1 arteriovenous fistulae was ligated, normalizing flow through the ipsilateral graft while maintaining high flow in the contralateral graft. The experimental groups received a blocking antibody to PDGFR-alpha (Ab-PDGFR-alpha; 10 mg/kg; n=5) or PDGFR-beta (Ab-PDGFR-beta; 10 mg/kg; n=6) by pulsed intravenous administration 30 minutes before ligation and at 4, 8, 15, and 22 days after ligation. Controls received carrier medium alone (n=8). Serum antibody concentrations were followed. Grafts were harvested after 28 days and analyzed by videomorphometry. Serum Ab-PDGFR-alpha concentrations fell rapidly after day 7 to 0, whereas serum Ab-PDGFR-beta concentrations were maintained at the target levels (>50 microg/mL). Compared with controls (3.7+/-0.3), the ratio of the intimal areas (normalized flow/high flow) was significantly reduced in Ab-PDGFR-beta (1.2+/-0.2, P<0.01) but not in Ab-PDGFR-alpha (2.2+/-0.4). Ab-PDGFR-alpha decreased significantly the overall smooth muscle cell nuclear density of the neointima (P<0.01) compared with either the control or Ab-PDGFR-beta treated groups. PDGFR-beta is necessary for flow-induced neointimal formation in prosthetic grafts. Targeting PDGFR-beta may be an effective pharmacological strategy for suppressing graft neointimal development.

In pulmonary arterial hypertension, plexiform lesions are associated with severe arterial obstruction and right ventricular failure. Exploring their structure and position is crucial for understanding the interplay between hemodynamics and vascular remodeling. The aim of this research was to use synchrotron-based phase contrast micro-CT to study the three-dimensional structure of plexiform lesions. Archived paraffin-embedded tissue-samples from 14 patients with pulmonary arterial hypertension (13 idiopathic, 1 with known BMPR2-mutation) were imaged. Clinical data showed high median PVR (12,5 WU) and mPAP (68 mmHg). Vascular lesions with more than one lumen were defined as plexiform. Prior radiopaque dye injection in some samples facilitated 3D-rendering. Four distinct types of plexiform lesions were identified: (1) localized within or derived from monopodial branches (supernumerary arteries), often with connection to the vasa vasorum; (2) localized between pulmonary arteries and larger airways as a tortuous transformation of intrapulmonary bronchopulmonary anastomoses; (3) as spherical structures at unexpected abrupt ends of distal pulmonary arteries; and (4) as occluded pulmonary arteries with re-canalization. By appearance and localization, types 1-2 potentially relieve pressure via the bronchial circulation, as pulmonary arteries in these patients were almost invariably occluded distally. In addition, types 1-3 were often surrounded by dilated thin-walled vessels, often connected to pulmonary veins, peri-bronchial vessels or the vasa vasorum. Collaterals, by-passing completely occluded pulmonary arteries, were also observed to originate within plexiform lesions. In conclusion, synchrotron-based imaging revealed significant plexiform lesion heterogeneity, resulting in a novel classification. The four types likely have different effects on hemodynamics and disease progression.

Objective-Vascular smooth muscle cells (SMCs), activated by growth factors after arterial injury, migrate and proliferate to expand the intima of the blood vessel. During intimal expansion, proliferation is suppressed and an increasingly large proportion of the neointimal mass is composed of newly synthesized extracellular matrix (ECM). We sough to determine whether the ECM heparan sulfate proteoglycan (HSPG) perlecan, which inhibits SMC proliferation in vitro, also accumulates and limits SMC proliferation during neointimal expansion. Methods and Results-Perlecan expression and accumulation were analyzed by immunohistochemistry and in situ hybridization during neointima formation after balloon catheter injury to the rat carotid artery. Perlecan expression was low in uninjured vessels and up to 7 days after injury, during maximal SMC proliferation. By 14 days after injury, perlecan was dramatically increased, and immunostaining remained heavy throughout the advanced lesion, 35 to 42 days after injury. Finally, explants of intimal tissue from 35-to 42-day neointimal lesions were digested with glycosaminoglycanases to determine whether endogenous HSPGs inhibit intimal SMC proliferation. SMCs within HS-depleted, but not chondroitinase ABC-treated or mock-incubated, explants were found to proliferate in response to plateletderived growth factor BB. Key Words: heparan sulfate Ⅲ perlecan Ⅲ neointimal hyperplasia Ⅲ vascular smooth muscle Ⅲ proliferation A ccumulated evidence indicates that extracellular matrix (ECM) proteins provide both permissive and inhibitory modulation of the cellular responses to growth factors. [1][2][3] Thus, changes in the amounts and types of ECM proteins that are deposited during the development of the atherosclerotic lesion may modify the effects of growth factors during vascular pathogenesis. However, mechanisms by which the ECM may inhibit intimal smooth muscle cell (SMC) proliferation in the ECM-rich advanced lesion remain unresolved. Considerable previous work has suggested that the glycosaminoglycan chains of heparan sulfate proteoglycans (HSPGs), and heparin, are potent inhibitors of SMC proliferation in vitro. 4 -6 Conversely, HS lyases appear to accelerate the conversion of the SMC phenotype from a quiescent, contractile state to a rapidly growing, "synthetic" state. 7 Pioneering studies demonstrated that heparin infusion dramatically suppresses the early wave of medial SMC proliferation that is required for the formation of a neointima after injury to the rat carotid artery. 8 Moreover, heparin was found to inhibit SMC cell growth in vitro, 9,10 suggesting that heparinlike molecules, such as vascular HSPGs, may be endogenous inhibitors of vascular SMC proliferation. Conclusions-HSPGsProteoglycans are among the ECM proteins that are deposited within the late neointimal lesion. [11][12][13][14] Perlecan is an ECM HSPG that is a potent modulator of cellular phenotype and proliferation 3,15,16 and a major vascular wall basement membrane component. 17,18 The induction of perlecan expres...