Arterial shear stress reduces eph-b4 expression in adult human veins.

Vein graft adaptation to the arterial environment is characterized by loss of venous identity, with reduced Ephrin type-B receptor 4 (Eph-B4) expression but without increased Ephrin-B2 expression. We examined changes of vessel identity of human saphenous veins in a flow circuit in which shear stress could be precisely controlled. Medium circulated at arterial or venous magnitudes of laminar shear stress for 24 hours; histologic, protein, and RNA analyses of vein segments were performed. Vein endothelium remained viable and functional, with platelet endothelial cell adhesion molecule (PECAM)-expressing cells on the luminal surface. Venous Eph-B4 expression diminished (p = .002), Ephrin-B2 expression was not induced (p = .268), and expression of osteopontin (p = .002) was increased with exposure to arterial magnitudes of shear stress. Similar changes were not found in veins placed under venous flow or static conditions. These data show that human saphenous veins remain viable during ex vivo application of shear stress in a bioreactor, without loss of the venous endothelium. Arterial magnitudes of shear stress cause loss of venous identity without gain of arterial identity in human veins perfused ex vivo. Shear stress alone, without immunologic or hormonal influence, is capable of inducing changes in vessel identity and, specifically, loss of venous identity.

Reduced adult endothelial cell EphB4 function promotes venous remodeling.

Reduced EphB4 expression is observed during vein graft adaptation and is associated with increased venous wall thickening. These findings suggest that EphB4 may mediate normal adult venous endothelial cell (EC) function and vein graft adaptation. We therefore tested the functional significance of EphB4 using EC with genetically reduced EphB4 signaling. EC were isolated from EphB4(+/+) and EphB4(+/-) mice. In vitro function was assessed through EC proliferation, migration, nitric oxide (NO) synthesis, and chemokine production. A mouse vein graft model was used to correlate in vitro findings with in vivo vein grafts. Smooth muscle cells (SMC) were subjected to proliferation and migration assays using EphB4(+/+) and EphB4(+/-) EC-conditioned medium. EphB4(+/-) EC exhibited diminished proliferation (P < 0.0001, n = 6), migration (P < 0.0001, n = 3), and NO production (P = 0.0012, n = 3). EphB4(+/-) EC had increased VEGF-A mRNA (P = 0.0006, n = 6) and protein (P = 0.0106, n = 3) as well as increased secretion of VEGF-A (P = 0.0010, n = 5), PDGF-BB (P < 0.0001, n = 6), and TGF-ß1 (P < 0.0001, n = 6). EphB4(+/-)-conditioned medium promoted SMC proliferation (P < 0.0001, n = 7) and migration (P = 0.0358, n = 3). Vein grafts and EphB4(+/-) EC showed similarity with regard to VEGF-A and eNOS mRNA and protein expression. In conclusion, reduced venous EC EphB4 function is associated with a proangiogenic and mitogenic phenotype. EphB4(+/-) EC have increased secretion of SMC mitogens and reduced NO production that correlate with the thickened neointima formed during vein graft adaptation. These findings suggest that EphB4 remains active in adult venous EC and that loss of EphB4 plays a role in vein graft adaptation.

Vascular endothelial growth factor-A inhibits EphB4 and stimulates delta-like ligand 4 expression in adult endothelial cells.

BACKGROUND: During vein graft adaptation to the arterial circulation, vascular endothelial growth factor (VEGF) A expression transiently increases before becoming downregulated; however, the role of VEGF-A in venous remodeling is not clear. In addition, although VEGF-A stimulates angiogenesis and determines arterial identity in nascent arterial endothelial cells (EC), the role of VEGF-A in regulating identity in adult venous EC is also not clear. MATERIALS AND METHODS: EC, wild type (EphB4+/+) or heterozygous knockout (EphB4+/-), were stimulated with VEGF-A (0-100 ng/mL) and examined with quantitative polymerase chain reaction and western blotting. RESULTS: VEGF-A (100 ng/mL) inhibited expression of EphB4 and stimulated expression of delta-like ligand 4 (dll4) but did not stimulate either notch or EphrinB2 expression in adult venous EC. Pretreatment with VEGF receptor 2-neutralizing antibody abolished VEGF-stimulated downregulation of EphB4 but not the upregulation of dll4. Pretreatment with PD98059 or wortmannin showed that VEGF-A downregulation of EphB4 and upregulation of dll4 are mitogen-activated protein kinase kinase and extracellular signal-regulated kinase dependent but phosphatidylinositol 3 kinase-Akt independent. Compared with VEGF-induced EphB4 downregulation and dll4 upregulation in control EC, reduced EphB4 signaling in EphB4+/- EC showed even further downregulation of EphB4 and upregulation of dll4. CONCLUSIONS: Despite the genetic programming of arterial and venous EC fate, VEGF-A can repress venous identity in adult venous EC without induction of arterial identity. These changes in adult EC in vitro recapitulate the changes in identity described during vein graft adaptation to the arterial environment in vivo.

Allogeneic human tissue-engineered blood vessel.

BACKGROUND: Arterial bypass graft implantation remains the primary therapy for patients with advanced cardiovascular disease; however, there is no available synthetic small-diameter vascular graft. METHODS: Tissue-engineered vessels were grown from human smooth muscle cells that were seeded on a biodegradable scaffold using a biomimetic perfusion system. The human tissue-engineered vessels (hTEV) were decellularized by a two-step process using a combination of detergents and hypertonic solutions. The mechanical characteristics were assessed by suture retention strength and burst pressure. The decellularized hTEV were implanted as aortic interpositional grafts in nude rats to evaluate in vivo performance as an arterial graft over a 6-week period. RESULTS: The human tissue-engineered structure formed a vessel composed of smooth muscle cells and the extracellular matrix proteins, including collagen. After decellularization, the collagen matrix remained intact while the cellular components were removed. The mechanical strength of the hTEV after decellularization was similar to human vein in vitro, with a burst pressure of 1,567 ± 384 mm Hg (n = 3) versus 1,680 ± 307 mm Hg for human saphenous vein. The hTEVs had a high patency rate (four of five grafts) without evidence of rupture or aneurysm over a 6-week period as an aortic interpositional graft in a nude rat model. Histologic analysis showed a thin neointima with a confluent endothelium and a subendothelial layer of smooth muscle cells on the explanted tissue-engineered vessels. Transmission electron microscopy on the explanted tissue demonstrated elastin formation in the neointima and intact residual collagen fibers from the tissue-engineered vessel. CONCLUSIONS: The hTEV had a high patency rate and remained mechanically stable as an aortic interpositional graft in a nude rat. The vessel supported the growth of a neointima with endothelial cells and smooth muscle cells. The host remodeling suggested the engineered matrix had a positive effect to create a regenerated vascular graft.

Age-related Notch-4 quiescence is associated with altered wall remodeling during vein graft adaptation.

BACKGROUND: The link of aging to specific mechanisms of vascular biology is not well understood. We have previously shown that aging is associated with increased vein graft wall thickness and that this process involves the VEGF-Delta/Notch-ephrin/Eph cascade. Therefore, we examined whether Dll-4 or Notch-4 are differentially expressed, according to age, during vein graft adaptation. MATERIALS AND METHODS: Vein grafts were performed in 6-mo and 24-mo Fischer 344 rats. Gene expression was analyzed by quantitative real-time PCR, and the distribution of Dll-4 and Notch-4 was observed by immunofluorescence. RESULTS: The expression of Dll-4 and Notch-4 was reduced in vein grafts performed in aged rats compared with the expression in young adult rats. Both Dll-4 and Notch-4 were distributed in vein graft endothelium as well as the outer adventitia, with reduced amounts in the outer adventitia of aged vein grafts. Aged veins had reduced eNOS membrane targeting and colocalization with caveolin-1 as well as reduced eNOS protein expression in comparison to young adult veins. In an exchange model between young and aged animals, heterogeneous vein grafts (Yo(Ag) and Ag(Yo)) showed significantly thicker neointima compared with young (Yo(Yo)) controls, and had Notch-4-positive cells, but not Dll-4-positive cells, diminished in the adventitia. Vein grafts that were air-denuded of endothelium did not show any adaptation to the arterial environment and also lacked both Dll-4 and Notch-4 expression at 3 wk. CONCLUSIONS: During vein graft adaptation to the arterial environment, both Dll-4 and Notch-4 expression are down-regulated in an aged, but not a young, background. Loss of Notch-4 is associated with loss of attenuation of neointima. The delta-Notch signaling pathway may be active during vein graft adaptation.

Elevated monocytes in patients with critical limb ischemia diminish after bypass surgery.

BACKGROUND: Mononuclear cells (MNC) increase neovascularization and ulcer healing after injection into an ischemic extremity. Circulating MNC are composed of lymphocytes (85%), monocytes (15%), and endothelial progenitor cells (EPC; 0.03%). We hypothesized that ischemic limbs secrete paracrine signals to recruit bone marrow-derived monocytes and EPC into the circulation, such that patients with critical limb ischemia (CLI) have increased circulating monocytes compared with control patients. We also hypothesized that circulating monocytes and EPC recruitment decrease after resolution of ischemia with successful revascularization. METHODS: We reviewed the records of all patients at the VA Connecticut Healthcare System undergoing primary, functionally successful, lower extremity peripheral bypass surgery between 2002 and 2007, but only including patients with both preoperative and postoperative (>4 mo) complete blood counts with differentials. RESULTS: Patients with CLI (n = 24) had elevated preoperative monocyte counts compared with control patients (n = 8) (0.753 ± 0.04 versus 0.516 ± 0.05; P = 0.0046), whereas the preoperative lymphocyte counts were not significantly different. After revascularization, ischemic patients had decreased monocyte counts compared with control patients (-20% versus + 55%; P = 0.0003), although lymphocyte counts were unchanged in both groups. Diabetic patients also had reduced postoperative monocyte counts (-32% versus + 13%; P = 0.035). Multivariable logistic regression demonstrated that the only factor that independently predicted reduced postoperative monocyte count was preoperative CLI (P = 0.038). CONCLUSIONS: Patients with CLI have increased numbers of circulating monocytes, and the monocyte number decreases with resolution of ischemia after successful revascularization. Circulating monocytes may be a clinically useful perioperative marker in patients with CLI undergoing vascular surgery.

Basic data related to surgical infrainguinal revascularization procedures: a twenty year update.

In 1990, Dalman and Taylor published a compilation of reported data that were identified by them as related to infrainguinal revascularization procedures in peripheral vascular surgery during the decade of the 1980s. The intervening 20 years has seen revolutionary advances in the field of peripheral vascular surgery, especially in the adoption of endovascular techniques, and an explosion of data related to emerging technologies in the field of infrainguinal revascularization. The tables in this manuscript reflect the evolution of our surgical knowledge during the turn of the 21st century. The superior patency of autologous saphenous vein in all positions is reaffirmed.

Vasodilator response correlates with outcome in chronic critical limb ischemia.

BACKGROUND: There are few predictors of limb salvage in patients with critical limb ischemia (CLI). We evaluated the accuracy of correlation of skin perfusion pressure (SPP) measurements in response to vasodilation to clinical outcome. METHODS: Patients with CLI were evaluated by SPP at baseline. After injection of the vasodilator alprostadil, SPP was re-evaluated at 120 min and at day 7. RESULTS: Patients showing clinical improvement demonstrated increased SPP in response to vasodilation (120 min: 34.12+/-2.44 to 48.33+/-3.41 mm Hg, P < 0.01; day 7: 33.13+/-3.14 to 45.83+/-3.79 mm Hg, P < 0.01), whereas patients who clinically deteriorated demonstrated no increase in SPP (120 min: 30.00+/-2.67 to 35.00+/-2.31 mm Hg, P = 0.086; day 7: 35.00+/-3.54 to 27.5+/-4.33 mm Hg, P = 0.22). CONCLUSIONS: Prognosis for limb salvage correlated with SPP improvement post-vasodilator treatment after both early and late time points. Measurement of SPP after vasodilator treatment may be clinically useful in the treatment of patients with CLI. A multi-center trial of SPP in response to vasodilators is warranted.

Endovascular revascularization of diseased native arteries following failed aortoiliac and femoropoliteal grafts: report of two cases.

Arterial reconstructions for lower-extremity ischemia, comprising aortoiliac, aortofemoral, and femoropopoliteal bypasses, and other procedures, have an intrinsic tendency to fail as time elapses. Surgical approaches to arteries in patients who have failed bypass grafts are often rendered more difficult, or even impossible to use, by surgical scarring or infection. The authors report two cases in which the diseased native arteries treated with failed aortoiliac and femoropopliteal bypass grafts were successfully recanalized with primary stent placement. Our cases show that stent placement of the diseased native arteries can represent a possible option for the treatment of failed bypass grafts.

Mechanisms of vein graft adaptation to the arterial circulation: insights into the neointimal algorithm and management strategies.

For patients with coronary artery disease or limb ischemia, placement of a vein graft as a conduit for a bypass is an important and generally durable strategy among the options for arterial reconstructive surgery. Vein grafts adapt to the arterial environment, and the limited formation of intimal hyperplasia in the vein graft wall is thought to be an important component of successful vein graft adaptation. However, it is also known that abnormal, or uncontrolled, adaptation may lead to abnormal vessel wall remodeling with excessive neointimal hyperplasia, and ultimately vein graft failure and clinical complications. Therefore, understanding the venous-specific pathophysiological and molecular mechanisms of vein graft adaptation are important for clinical vein graft management. Of particular importance, it is currently unknown whether there exist several specific distinct molecular differences in the venous mechanisms of adaptation that are distinct from arterial post-injury responses; in particular, the participation of the venous determinant Eph-B4 and the vascular protective molecule Nogo-B may be involved in mechanisms of vessel remodeling specific to the vein. This review describes (1) venous biology from embryonic development to the mature quiescent state, (2) sequential pathologies of vein graft neointima formation, and (3) novel candidates for strategies of vein graft management. Scientific inquiry into venous-specific adaptation mechanisms will ultimately provide improvements in vein graft clinical outcomes.

Surgically implantable magnetic resonance angiography coils improve resolution to allow visualization of blood flow dynamics.

BACKGROUND: Magnetic resonance angiography (MRA) is clinically useful but of limited applicability to small animal models due to poor signal resolution, with typical voxel sizes of 1 mm(3) that are insufficient to analyze vessels of diameter <1 mm. We determined whether surgically implantable, extravascular MRA coils increase signal resolution adequately to examine blood flow dynamics METHODS: A custom MRA coil was surgically implanted near the carotid artery of a New Zealand White rabbit. A stenosis was created in the carotid artery to induce complicated, non-laminar flow. Phase contrast images were obtained on multiple axial planes with 3T MRA and through-plane velocity profiles were calculated under laminar and complicated flow conditions. These velocity profiles were fit to a laminar flow model using ordinary least squares in order to quantify the degree of flow complication (Matlab). Flow was also measured with a Doppler flow probe; vessel diameters and flow velocities were compared with duplex ultrasound RESULTS: Carotid artery blood flow was 24.7 +/- 2.6 ml/min prior to stenosis creation and reduced to 12.0 +/- 1.7 ml/min following injury (n=3). An MRA voxel size of 0.1 x 0.1 x 5 mm was achieved. The control carotid artery diameter was 1.9 +/- 0.1 mm, and cross-sectional images containing 318 +/- 22 voxels were acquired (n=26). Velocity profiles resembled laminar flow proximal to the stenosis, and then became more complicated just proximal and distal to the stenosis. Laminar flow conditions returned downstream of the stenosis CONCLUSION: Implantable, extra-vascular coils enable small MRA voxel sizes to reproducibly calculate complex velocity profiles under both laminar and complicated flow in a small animal model. This technique may be applied to study blood flow dynamics of vessel remodeling and atherogenesis.

Primary stent placement for iliac artery chronic total occlusions.

PURPOSE: The purpose of this study was to evaluate the technical and mid-term results of primary stent placement for chronic total occlusions (CTO) of the iliac artery, in comparison to stent placement for iliac artery stenosis. METHODS: A retrospective study was carried out on 114 consecutive limbs with 24 CTOs and 90 stenoses of the iliac artery that underwent primary stent placement. Primary, assisted primary patency, and limb salvage rates were determined in accordance with the Society for Vascular Surgery guidelines. RESULTS: Angiographic and intravascular ultrasonographic success was achieved in all 114 limbs (100%). Three major complications, including 1 distal embolism and 2 arterial ruptures, occurred in the CTO group. The 2-year primary patency rate in the CTO group was as high as that observed in the stenosis group (91% vs 89%). There were also no significant differences in the assisted primary patency, limb salvage, and survival rates between the two groups. CONCLUSIONS: Our results indicate that primary stent placement is a safe and effective treatment for iliac CTOs. However, major complications, including distal embolization and iliac artery rupture, remain a significant problem, and caution should therefore be exercised when performing this technique for iliac CTOs.

Patches for carotid artery endarterectomy: current materials and prospects.

Patch angioplasty is commonly performed after carotid endarterectomy. Randomized prospective trials and meta-analyses have documented improved rates of perioperative and long-term stroke prevention as well as reduced rates of restenosis for patches compared with primary closure of the arteriotomy. Although use of vein patches is considered to be the gold standard for patch closure, newer generations of synthetic and biologic materials rival outcomes associated with vein patches. Future bioengineered patches are likely to optimize patch performance, both by achieving minimal stroke risk and long-term rates of restenosis as well as by minimizing the risk of unusual complications of prosthetic patches such as infection and pseudoaneurysm formation. In addition, lessons from bioengineered patches will likely enable construction of bioengineered and tissue-engineered bypass grafts.

Limb ischemia after iliac ligation in aged mice stimulates angiogenesis without arteriogenesis.

OBJECTIVE: Older patients are thought to tolerate acute ischemia more poorly than younger patients. Since aging may depress both angiogenesis and arteriogenesis, we determined the effects of age on both angiogenesis and arteriogenesis in a model of severe acute limb ischemia. METHODS: Young adult (3-months-old) and aged (18-months-old) C57BL/6 mice underwent right common iliac artery and vein ligation and transection. Data were collected on days 0, 7, and 14. Perfusion was measured with a laser Doppler scan and compared to the contralateral limb. Functional deficits were evaluated with the Tarlov scale. Capillary density and endothelial progenitor cell (EPC) number were determined by direct counting lectin-positive/alpha-actin-negative cells and VEGFR2/CXCR4 dually-positive cells, respectively; angiography was performed to directly assess arteriogenesis. RESULTS: Young adult and aged mice had a similar degree of decreased perfusion after iliac ligation (young, n = 15: 20.4 +/- 1.9%, vs aged, n = 20: 19.6 +/- 1.3%; P = .72, analysis of variance [ANOVA]); however, young mice recovered faster and to a greater degree than aged mice (day 7, 35 +/- 6% vs 17 +/- 4%, P = .046; day 14, 60 +/- 5% vs 27 +/- 7%, P = .0014). Aged mice had worse functional recovery by day 14 compared to young mice (2.3 +/- 0.3 vs 4.3 +/- 0.4; P = .0021). Aged mice had increased capillary density (day 7, 12.9 +/- 4.4 vs 2.8 +/- 0.3 capillaries/hpf; P = .02) and increased number of EPC incorporated into the ischemic muscle (day 7, 8.1 +/- 0.9 vs 2.5 +/- 1.9 cells; P = .007) compared to young mice, but diminished numbers of collateral vessels to the ischemic limb (1 vs 9; P = .01), as seen on angiography. CONCLUSION: After severe hind limb ischemia, aged animals become ischemic to a similar degree as young animals, but aged animals have significantly impaired arteriogenesis and functional recovery compared to younger animals. These results suggest that strategies to stimulate arteriogenesis may complement those that increase angiogenesis, and may result in improved relief of ischemia.

Primary stent placement for late complete occlusion after aortoiliac reconstructive surgery: report of a case.

We report a case that was successfully treated by primary stent placement without thrombolysis or thrombectomy for graft thrombosis after aortoiliac reconstructive surgery. A 79-year-old man presented with a 2-month history of severe intermittent claudication of the right leg. He had undergone a surgical repair of abdominal aortic aneurysm with a bifurcated polyester graft 3 years before presentation. Digital subtraction angiography revealed total occlusion of the right limb of the graft. He underwent primary stent placement on the lesion, and completion angiography showed revascularization of the right limb. Primary stent placement can be performed to decrease the risks of surgery and increase the salvage of a graft with chronic total occlusion.

Deep venous thrombosis caused by congenital absence of the inferior vena cava: report of a case.

Although anomalies of the inferior vena cava (IVC) are seen frequently in a clinical setting, congenital absence of the IVC (AIVC) is rare. However, anomalies of the IVC should be considered in young patients suffering from recurrent and idiopathic DVT. We report a case of DVT possibly caused by AIVC in a 27-year-old man, and discuss the clinical features, diagnosis, and treatment of this unusual entity.

Laminar shear stress stimulates vascular smooth muscle cell apoptosis via the Akt pathway.

Vascular smooth muscle cells (SMC) may be directly exposed to blood flow after an endothelial-denuding injury. It is not known whether direct exposure of SMC to shear stress reduces SMC turnover and contributes to the low rate of restenosis after most vascular interventions. This study examines if laminar shear stress inhibits SMC proliferation or stimulates apoptosis. Bovine aortic SMC were exposed to arterial magnitudes of laminar shear stress (11 dynes/cm(2)) for up to 24 h and compared to control SMC (0 dynes/cm(2)). SMC density was assessed by cell counting, DNA synthesis by (3)[H]-thymidine incorporation, and apoptosis by TUNEL staining. Akt, caspase, bax, and bcl-2 phosphorylation were assessed by Western blotting; caspase activity was also measured with an in vitro assay. Analysis of variance was used to compare groups. SMC exposed to laminar shear stress had a 38% decrease in cell number (n = 4, P = 0.03), 54% reduction in (3)[H]-thymidine incorporation (n = 3, P = 0.003), and 15-fold increase in TUNEL staining (n = 4, P < 0.0001). Akt phosphorylation was reduced by 67% (n = 3, P < 0.0001), whereas bax/bcl-2 phosphorylation was increased by 1.8-fold (n = 3, P = 0.01). Caspase-3 activity was increased threefold (n = 5, P = 0.03). Pretreatment of cells with ZVAD-fmk or wortmannin resulted in 42% increased cell retention (n = 3, P < 0.01) and a fourfold increase in apoptosis (n = 3, P < 0.04), respectively. Cells transduced with constitutively-active Akt had twofold decreased apoptosis (n = 3, P < 0.002). SMC exposed to laminar shear stress have decreased proliferation and increased apoptosis, mediated by the Akt pathway. These results suggest that augmentation of SMC apoptosis may be an alternative strategy to inhibit restenosis after vascular injury.

Endothelial nitric oxide synthase stimulates aneurysm growth in aged mice.

BACKGROUND/AIMS: Age-associated changes in endothelial nitric oxide synthase (eNOS) expression have not been definitively linked to the pathophysiology of aortic aneurysms. We examined the role of eNOS in human patients and an age-appropriate mouse model. METHODS: eNOS transcripts and immunodetectable protein were assessed by quantitative PCR and immunohistochemistry in human ascending thoracic aneurysms (n = 29) and referent aortae (n = 31). Carotid aneurysms were induced with CaCl2 in young adult (3 months) and aged (18 months) C57BL/6 and eNOS-knockout (eNOS-KO) mice. RESULTS: eNOS transcripts and protein were reduced in human aneurysms compared with controls, although aortic eNOS expression also decreased with patient age. Aged wild-type mice had significantly larger aneurysm diameter than young adult mice. Aged wild-type mice had reduced eNOS transcripts and protein compared with young adult mice. Aged eNOS-KO mice had smaller aneurysms compared with aged wild-type mice but similar size aneurysms compared with young eNOS-KO and young wild-type mice. CONCLUSION: eNOS expression is reduced in both aged human and aged mouse endothelium and eNOS expression is linked to aneurysm expansion in aged but not young adult mice. These findings support the relevance of age-associated changes in eNOS expression in clinical aneurysmal disease.

Venous identity is lost but arterial identity is not gained during vein graft adaptation.

OBJECTIVES: Ephrin ligands and Eph receptors are signaling molecules that are differentially expressed on arteries and veins during development. We examined whether Eph-B4, a venous marker, and Ephrin-B2, an arterial marker, are regulated during vein graft adaptation in humans and aged rats. METHODS AND RESULTS: Eph-B4 transcripts and immunodetectable protein are downregulated in endothelial and smooth muscle cells of patent vein grafts in both humans and in aged rats, whereas Ephrin-B2 transcripts and protein are not strongly induced. Other markers of arterial identity, including dll4 and notch-4, are also not induced during vein graft adaptation in aged rats. Because VEGF-A is upstream of the Ephrin-Eph pathway, and expression of VEGF-A is induced only at early time points after exposure of the vein to the arterial environment, we inhibited VEGF-A in vein grafts using an siRNA-based approach. Vein grafts treated with siRNA directed against VEGF-A demonstrated a thicker intima-media containing alpha-actin, consistent with arterialization, but did not contain Eph-B4 or Ephrin-B2. CONCLUSIONS: Venous identity is preserved in the veins of aged animals, but is lost during adaptation to the arterial circulation; arterial markers are not induced. Markers of vessel identity are plastic in adults and their selective regulation may mediate vein graft adaptation to the arterial environment in aged animals and humans.

Evidence supporting changes in Nogo-B levels as a marker of neointimal expansion but not adaptive arterial remodeling.

Both neointimal hyperplasia and inward remodeling contribute to restenosis and lumen loss. Nogo-B has been recently described as an inhibitor of vascular injury and neointimal hyperplasia. To determine whether Nogo-B expression may be a mediator of inward remodeling, we examine the localization of expression of Nogo-B in an in vivo model that examines both neointimal hyperplasia and inward remodeling. The rabbit carotid artery was subjected to balloon injury, outflow branch ligation to reduce flow, or both balloon injury and reduction in flow. In balloon injury-induced neointimal hyperplasia Nogo-B expression was reduced in the intima and media but stimulated in the adventitia. In low flow-induced inward remodeling medial Nogo-B expression was not reduced and adventitial Nogo-B expression was not stimulated. Low flow significantly augmented balloon injury-induced neointimal hyperplasia and was accompanied by reduced intimal and medial Nogo-B expression, and increased adventitial Nogo-B expression in both smooth muscle cells and macrophages. Low flow-induced inward remodeling is not associated with changes in medial Nogo-B expression and is distinct from injury-induced neointimal hyperplasia. Pharmacological strategies to inhibit neointimal hyperplasia and restenosis using normal flow models may only partially account for lumen loss and therefore may not accurately predict responses in patients with extensive outflow disease.