Hypoxic perfusion of pulmonary arterial vasa vasorum increases pulmonary arterial pressure.

The pathophysiology of pulmonary hypertension (PH) is not fully understood. Here, we tested the hypothesis that hypoxic perfusion of the vasa vasorum of the pulmonary arterial (PA) wall causes PH. Young adult pig lungs were explanted and placed into a modified ex vivo lung perfusion unit (organ care system, OCS) allowing the separate adjustment of parameters for mechanical ventilation, as well as PA perfusion and bronchial arterial (BA) perfusion. The PA vasa vasorum are branches of the BA. The lungs were used either as the control group (n = 3) or the intervention group (n = 8). The protocol for the intervention group was as follows: normoxic ventilation and perfusion (steady state), hypoxic BA perfusion, steady state, and hypoxic BA perfusion. During hypoxic BA perfusion, ventilation and PA perfusion maintained normal. Control lungs were kept under steady-state conditions for 105 min. During the experiments, PA pressure (PAP) and blood gas analysis were frequently monitored. Hypoxic perfusion of the BA resulted in an increase in systolic and mean PAP, a reaction that was reversible upon normoxic BA perfusion. The PAP increase was reproducible during the second hypoxic BA perfusion. Under control conditions, the PAP stayed constant until about 80 min of the experiment. In conclusion, the results of the current study prove that hypoxic perfusion of the vasa vasorum of the PA directly increases PAP in an ex situ lung perfusion setup, suggesting that PA vasa vasorum function and wall ischemia may contribute to the development of PH.NEW & NOTEWORTHY Hypoxic perfusion of the vasa vasorum of the pulmonary artery directly increased pulmonary arterial pressure in an ex vivo lung perfusion setup. This suggests that the function of pulmonary arterial vasa vasorum and wall ischemia may contribute to the development of pulmonary hypertension.

Local adventitial anti-angiogenic gene therapy reduces growth of vasa-vasorum and in-stent restenosis in WHHL rabbits.

BACKGROUND: Antiproliferative drugs in drug eluting stents (DES) are associated with complications due to impaired re-endothelialization. Additionally, adventitial neovascularization has been suggested to contribute to in-stent restenosis (ISR). Since Vascular Endothelial Growth Factors (VEGFs) are the key mediators of angiogenesis, we investigated feasibility and efficacy of local gene therapy for ISR utilizing soluble decoy VEGF receptors to reduce biological activity of adventitial VEGFs. METHOD: Sixty-nine adult WHHL rabbit aortas were subjected to endothelial denudation. Six weeks later catheter-mediated local intramural infusion of 1.5x10e10 pfu adenoviruses encoding soluble VEGF Receptor-1 (sVEGFR1), sVEGFR2, sVEGFR3 or control LacZ and bare metal stent implantation were performed in the same aortic segment. Marker protein expression was assessed at 6d in LacZ cohort. Immunohistochemistry, morphometrical analyses and angiography were performed at d14, d42 and d90. RESULTS: Transgene expression was localized to adventitia. All decoy receptors reduced the size of vasa-vasorum at 14d, AdsVEGFR2 animals also had reduced density of adventitial vasa-vasorum, whereas AdsVEGFR3 increased the density of vasa-vasorum. At d42, AdsVEGFR1 and AdsVEGFR2 reduced ISR (15.7 ±â€¯6.9% stenosis, P < 0.01 and 16.5 ±â€¯2.7%, P < 0.05, respectively) vs. controls (28.3 ±â€¯7.6%). Moreover, AdsVEGFR-3 treatment led to a non-significant trend in the reduction of adventitial lymphatics at all time points and these animals had significantly more advanced neointimal atherosclerosis at 14d and 42d vs. control animals. CONCLUSIONS: Targeting adventitial neovascularization using sVEGFR1 and sVEGFR2 is a novel strategy to reduce ISR. The therapeutic effects dissipate at late follow up following short expression profile of adenoviral vectors. However, inhibition of VEGFR3 signaling accelerates neoatherosclerosis.

Coronary endothelial dysfunction is associated with inflammation and vasa vasorum proliferation in patients with early atherosclerosis.

OBJECTIVE: Endothelial dysfunction is an early manifestation of atherosclerosis. Inflammation and vasa vasorum play a pivotal role in the pathophysiology of plaque initiation, development, and complications. Optical coherence tomography allows high-resolution imaging of tissue microstructure. Therefore, the aim of this study was to test the hypothesis that segments with endothelial dysfunction show macrophages and vasa vasorum in patients with early coronary artery disease. APPROACH AND RESULTS: Optical coherence tomography images were obtained from 40 patients with mild coronary atherosclerosis who underwent coronary endothelial function assessment. Optical coherence tomography findings, including macrophages and microchannels, were evaluated in 76 coronary segments corresponding to those in endothelial response to acetylcholine. Coronary artery diameter change in response to acetylcholine was more severe in segments showing macrophages (-17.7±14.7% versus -6.3±13.9%; P<0.01) and microchannels (-15.9±15.9% versus -6.4±13.5%; P<0.01) than those without. There were increasing trends of the prevalence of macrophages and microchannels with endothelial dysfunction as stratified by quartiles of coronary artery diameter change (P<0.01 and P=0.02 for trend, respectively). In particular, segments with both macrophages and microchannels (n=12) tended to have worse endothelial function than those with macrophages alone (n=15) and microchannels alone (n=15; -22.1±14.6% versus -10.9±15.6% and -10.9±15.6%; P=0.07 and P=0.06, respectively). CONCLUSIONS: Epicardial endothelial dysfunction was associated with optical coherence tomography -identified macrophages and microchannels in mild coronary atherosclerosis. The current study further supports the role of inflammation and vasa vasorum proliferation in the early stage of coronary atherosclerosis.

High proliferative potential endothelial colony-forming cells contribute to hypoxia-induced pulmonary artery vasa vasorum neovascularization.

Angiogenic expansion of the vasa vasorum (VV) is an important contributor to pulmonary vascular remodeling in the pathogenesis of pulmonary hypertension (PH). High proliferative potential endothelial progenitor-like cells have been described in vascular remodeling and angiogenesis in both systemic and pulmonary circulations. However, their role in hypoxia-induced pulmonary artery (PA) VV expansion in PH is not known. We hypothesized that profound PA VV neovascularization observed in a neonatal calf model of hypoxia-induced PH is due to increased numbers of subsets of high proliferative cells within the PA adventitial VV endothelial cells (VVEC). Using a single cell clonogenic assay, we found that high proliferative potential colony-forming cells (HPP-CFC) comprise a markedly higher percentage in VVEC populations isolated from the PA of hypoxic (VVEC-Hx) compared with control (VVEC-Co) calves. VVEC-Hx populations that comprised higher numbers of HPP-CFC also demonstrated markedly higher expression levels of CD31, CD105, and c-kit than VVEC-Co. In addition, significantly higher expression of CD31, CD105, and c-kit was observed in HPP-CFC vs. the VVEC of the control but not of hypoxic animals. HPP-CFC exhibited migratory and tube formation capabilities, two important attributes of angiogenic phenotype. Furthermore, HPP-CFC-Co and some HPP-CFC-Hx exhibited elevated telomerase activity, consistent with their high replicative potential, whereas a number of HPP-CFC-Hx exhibited impaired telomerase activity, suggestive of their senescence state. In conclusion, our data suggest that hypoxia-induced VV expansion involves an emergence of HPP-CFC populations of a distinct phenotype with increased angiogenic capabilities. These cells may serve as a potential target for regulating VVEC neovascularization.

Pathophysiology of atherosclerosis plaque progression.

Atherosclerotic plaque rupture with luminal thrombosis is the most common mechanism responsible for the majority of acute coronary syndromes and sudden coronary death. The precursor lesion of plaque rupture is thought to be a thin cap fibroatheroma (TCFA) or "vulnerable plaque". TCFA is characterised by a necrotic core with an overlying thin fibrous cap (≤65 µm) that is infiltrated by macrophages and T-lymphocytes. Intraplaque haemorrhage is a major contributor to the enlargement of the necrotic core. Haemorrhage is thought to occur from leaky vasa vasorum that invades the intima from the adventitia as the intima enlarges. The early atherosclerotic plaque progression from pathologic intimal thickening (PIT) to a fibroatheroma is thought to be the result of macrophage infiltration. PIT is characterised by the presence of lipid pools which consist of proteoglycan with lipid insudation. The conversion of the lipid pool to a necrotic core is poorly understood but is thought to occur as a result of macrophage infiltration which releases matrix metalloproteinase (MMPs) along with macrophage apoptosis that leads to the formation of a acellular necrotic core. The fibroatheroma has a thick fibrous cap that begins to thin over time through macrophage MMP release and apoptotic death of smooth muscle cells converting the fibroatheroma into a TCFA. Other causes of thrombosis include plaque erosion which is less frequent than plaque rupture but is a common cause of thrombosis in young individuals especially women <50 years of age. The underlying lesion morphology in plaque erosion consists of PIT or a thick cap fibroatheroma. Calcified nodule is the least frequent cause of thrombosis, which occurs in older individuals with heavily calcified and tortious arteries.

Changes in CT angiographic opacification of porcine coronary artery wall with patchy altered flow in vasa vasorum.

To evaluate the potential of whole-body CT to detect localized areas of decreased or increased vascularity in coronary arterial walls. We used both microsphere embolization of coronary artery vasa vasorum to generate small areas of hypoperfusion and surrounding hyperperfusion of the arterial wall and diet-induced hypercholesterolemia. As a stimulus for localized angiogenesis, such as occurs in early plaque formation in the coronary arterial wall, microspheres were injected selectively into the LAD coronary artery lumens of anesthetized pigs. Fourteen pigs (acute) then had a segment of their LAD harvested during injection of contrast medium and snap-frozen for subsequent cryo-static micro-CT. An additional thirteen pigs (chronic) were allowed to recover, fed a high cholesterol diet and 3 months later were again anesthetized and a segment of the LAD artery harvested and scanned. The spatial distribution of the contrast agent within the arterial wall was measured in contiguous micro-CT images at right angles to the lumen axis with the area of wall in each cross-sectional image being approximately (0.1 mm)(3) in size. In the acute animals there were no localized areas of increased contrast around the hypoperfused embolized perfusion territories in the arterial wall, but in the chronic animals the hypoperfused areas were surrounded by increased contrast. These results suggest that CT might be able to detect localized regions of increased vascularity in the arterial wall as an indicator of early atherosclerotic stimulation of vasa vasorum proliferation.

Anti-angiogenic activity of rPAI-1(23) and vasa vasorum regression.

The vasa vasorum are unique networks of vessels that become angiogenic in response to changes in the vessel wall. Structural studies, using various imaging modalities, show that the vasa vasorum form a plexus of microvessels during the atherosclerotic disease process. The events that stimulate vasa vasorum neovascularization remain unclear. Anti-angiogenic molecules have been shown to inhibit/regress the neovascularization; they provide significant insight into vasa vasorum function, structure, and specific requirements for growth and stability. This review discusses evidence for and against potential stimulators of vasa vasorum neovascularization. Anti-angiogenic rPAI-123, a truncated isoform of plasminogen activator inhibitor-1 (PAI-1) stimulates a novel pathway for regulating plasmin activity. This mechanism contributes significantly to vasa vasorum regression/collapse and is discussed as a model of regression.

The vasa vasorum and associated endothelial nitric oxide synthase is more important for saphenous vein than arterial bypass grafts.

No-touch (NT) saphenous vein (SV) grafts are superior to SVs harvested by the conventional technique (CT), with a patency comparable with the internal thoracic artery (ITA). Preservation of the vasa vasorum is implicated in the success of NT harvesting. We compared the vasa vasorum and endothelial nitric oxide synthase (eNOS) in NT SV with ITA and radial artery (RA) grafts. Skeletonized SV (SSV) was also analyzed. The NT SV had a higher number and larger vasa vasorum compared with ITA (P = .0001) and RA (P = .0004) that correlated with eNOS protein. Activity of eNOS in SSV grafts was significantly lower than NT SV grafts (P = 004). Since a high proportion of the vasa vasorum are removed in SSV using the CT, we suggest that preservation of the vasa vasorum and eNOS-derived NO contributes to the high patency for NT as compared with SSV grafts.

The implication of vasa vasorum in surgical diseases of the aorta.

Vasa vasorum (VV) are microscopic vases that perfuse the vessel's wall; arteries and veins. Many recent researches support the opinion that VV have a significant role in aortic pathology. The VV, or 'the vessels of the vessels', form a network of microvessels that lie in the adventitia and penetrate the outer media of the host vessel wall. Although the importance of the VV in providing nutritional support is not well known, obstruction of blood flow through these vessels has been implicated in the pathogenesis of many cardiovascular diseases such as aortic intramural hematoma, aortic aneurysm, and acute or chronic aortic dissection. Although the proliferation of VV due to atherogenic stimuli is controversial, experimental and clinical studies strongly suggest the potential of VV in vascular proliferative disorders. It seems that the rupture of VV is implicated in intramural hematoma, which can develop in acute aortic dissection. In this review article, we would like to stress the anatomy and mainly the pathophysiology, and the implication of VV in the acute and chronic aortic pathologies.

OX40 ligand plays an important role in the development of atherosclerosis through vasa vasorum neovascularization.

AIMS: Atherosclerosis is characterized by infiltration of inflammatory cells and enhanced vasa vasorum formation, for which immunological mechanisms may be involved. OX40, a membrane-bound molecule of the tumour necrosis factor-receptor superfamily, is expressed by activated T-cells, while OX40 ligand (OX40L) is expressed in activated macrophages and endothelial cells. In this study, we thus examined whether the OX40/OX40L system is involved in the pathogenesis of atherosclerosis. METHODS AND RESULTS: We examined apolipoprotein E-deficient (ApoE(-/-)) mice and ApoE(-/-)/OX40L-double-deficient (ApoE(-/-)/OX40L(-/-)) mice fed on a high-fat diet for 8 weeks. The extent of aortic atheroma was significantly less in ApoE(-/-)/OX40L(-/-) mice compared with ApoE(-/-) mice. We also treated high-fat-fed ApoE(-/-) mice with or without MGP34 antibody (OX40L-specific neutralizing antibody) for 10 weeks. After the treatment, the extent of aortic atheroma was again significantly less in MGP34-treated mice compared with controls. Importantly, both vascular density in the aortic adventitia and vascular endothelial growth factor-induced angiogenesis in the Matrigel assay in vivo were significantly reduced in ApoE(-/-)/OX40L(-/-) mice compared with ApoE(-/-) mice. Finally, when high-fat-fed ApoE(-/-) mice were transplanted with bone marrow cells from either wild-type or OX40L(-/-) mice, the extent of aortic atheroma was comparable between the two groups. CONCLUSION: These results indicate that the vascular OX40/OX40L system plays an important role in the formation of vasa vasorum and subsequent atherosclerosis, suggesting that the vascular OX40/OX40L system might be a new therapeutic target of atherosclerosis.

Dysfunctional vasa vasorum in diabetic peripheral artery obstructive disease with critical lower limb ischaemia.

OBJECTIVES AND DESIGN: To establish whether in diabetic patients with peripheral artery obstructive disease (PAOD) vasa vasorum (vv) neoangiogenesis is altered with increased arterial damage. MATERIALS: Thirty-three patients with PAOD and critical lower limb ischaemia, 22 with type II diabetes. METHODS: Immunohistochemistry for endothelial cell markers (CD34 and von Willebrand Factor); real-time reverse transcription polymerase chain reaction (RT-PCR) to quantify arterial wall expression of vascular endothelial growth factor (VEGF); enzyme-linked immunosorbent assay (ELISA) to assess blood VEGF; flow cytometry to detect circulating endothelial cells (CECs). RESULTS: Patients with PAOD and diabetes have a higher frequency (60% vs. 45%) of advanced atherosclerotic lesions and a significant reduction (p = 0.0003) in CD34(+) capillaries in the arterial media. Adventitial neoangiogenesis was increased equally (CD34(+) and vWF(+)) in all patients. Likewise, all patients have increased CEC and VEGF concentration in the blood as well as in-situ VEGF transcript expression. CONCLUSIONS: Patients with PAOD have remarkable arterial damage despite increased in-situ and circulating expression of the pro-angiogenic VEGF; a dysfunctional vv angiogenesis was seen in diabetics which also showed a higher frequency of parietal damage; it is suggested that in diabetic arterial wall, injury is worsened by vv inability to finalise an effective VEGF-driven arterial wall neoangiogenesis.

Symptomatic enlargement of an occluded giant carotido-ophthalmic aneurysm after endovascular treatment: the vasa vasorum theory.

We describe a patient with a symptomatic left giant carotido-ophthalmic aneurysm who initially underwent coil embolization with subtotal obliteration. The patient's symptoms were initially stable, but 1 year later, she presented with a rapidly progressive contralateral visual deficit. Although angiogram showed a stable neck remnant, MR confirmed aneurysm growth and showed a new peripheral hematoma in the wall of the thrombosed aneurysm. Surgical exploration was undertaken, and even after trapping and intra-aneurysmal thrombectomy, constant bleeding was observed from the wall of the thrombosed aneurysm consistent with the vasa vasorum. Bleeding stopped after cauterization and partial resection of the aneurysm dome, and the aneurysm was clipped. The patient's recent visual deficit markedly improved, and the angiogram did not reveal any residue. Giant aneurysms may continue to grow due to a hypertrophic vasa vasorum and subadventitial hemorrhages. Surgery should be considered if complete thrombosis of the aneurysm does not alleviate patient's symptoms.

Frontiers in nephrology: early atherosclerosis--a view beyond the lumen.

Endothelial dysfunction is an established clinical marker of early coronary artery disease and has been shown to be associated with increased cardiovascular morbidity and mortality. New concepts now extend the view of endothelial dysfunction beyond the traditional involvement of the coronary arterial endothelium alone. Recent research indicates that the coronary vessel wall, especially the vasa vasorum, as well as bone marrow-derived endothelial progenitor cells may be subject to proatherosclerotic changes, even before the development of angiographically evident endothelial dysfunction; therefore, "microvascular endothelial dysfunction," which is composed of dysfunction of the vasa vasorum's endothelium as well as "microcellular endothelial dysfunction," reflecting impaired mobilization and function of endothelial progenitor cells, may precede "macrovascular endothelial dysfunction." Vasa vasorum neovascularization, with endothelial leakage and dysfunction increasing influx of proinflammatory and proatherogenic cellular and noncellular substances into the vessel wall, is proposed as one feature of this new concept. In addition, the role of bone marrow-derived endothelial progenitor cells is discussed as are the potential impact of impaired progenitor cell mobilization, release from the marrow, and function in acute and stable coronary artery disease. Finally, potential future therapies are proposed, focusing on interventions that may prevent or diminish the development of the microvascular and microcellular endothelial dysfunction.

Vascular ossification-calcification in metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and calciphylaxis-calcific uremic arteriolopathy: the emerging role of sodium thiosulfate.

BACKGROUND: Vascular calcification is associated with metabolic syndrome, diabetes, hypertension, atherosclerosis, chronic kidney disease, and end stage renal disease. Each of the above contributes to an accelerated and premature demise primarily due to cardiovascular disease. The above conditions are associated with multiple metabolic toxicities resulting in an increase in reactive oxygen species to the arterial vessel wall, which results in a response to injury wound healing (remodeling). The endothelium seems to be at the very center of these disease processes, acting as the first line of defense against these multiple metabolic toxicities and the first to encounter their damaging effects to the arterial vessel wall. RESULTS: The pathobiomolecular mechanisms of vascular calcification are presented in order to provide the clinician-researcher a database of knowledge to assist in the clinical management of these high-risk patients and examine newer therapies. Calciphylaxis is associated with medial arteriolar vascular calcification and results in ischemic subcutaneous necrosis with vulnerable skin ulcerations and high mortality. Recently, this clinical syndrome (once thought to be rare) is presenting with increasing frequency. Consequently, newer therapeutic modalities need to be explored. Intravenous sodium thiosulfate is currently used as an antidote for the treatment of cyanide poisoning and prevention of toxicities of cisplatin cancer therapies. It is used as a food and medicinal preservative and topically used as an antifungal medication. CONCLUSION: A discussion of sodium thiosulfate's dual role as a potent antioxidant and chelator of calcium is presented in order to better understand its role as an emerging novel therapy for the clinical syndrome of calciphylaxis and its complications.

Hypothesis: a potential role for the vasa vasorum in the maintenance of vein graft patency.

Autologous saphenous vein is the most commonly used conduit for coronary artery bypass surgery with more than 50% grafts occluding within 10 years. In conventional preparation the vein undergoes considerable surgical trauma with damage to the outer layers during harvesting. Within these regions are situated the vasa vasorum and small vessels providing oxygen and nutrients to the vessel wall. Certain vasa vasorum terminate in the vessel lumen where it is suggested that they have a physiological role. Preservation of the vasa vasorum of saphenous veins used as bypass conduits may play an important role in the maintenance of graft patency.

[Pathogenesis of atherosclerosis in patients with lipid metabolism disturbances: hypothesis on cholesterol utilization and atheromatous plaque formation]. / Patogenez ateroskleroza u bol'nykh bez narusheniia lipidnogo obmena: gipoteza utilizatsii kholesterina i obrazovaniia ateromatoznoi bliashki.

Cholesterol is known to participate in atheromatous plaque formation coming from blood stream and affecting vascular endothelium in environment of elevated low-density lipoproteins (LDL). Nevertheless, the occurrence of single atheromatous plaque evidences the possibility of local lipoprotein accumulation by vascular wall without systemic increase in serum LDLs. The author hypothesizes that in the absence of hypercholesterolemia atheroma can evolve through the utilization of modified LDL and free or etherified cholesterol, that remain in media non-removed by high density lipoproteins (HDL) owing to their structural damage after local vascular wall ischemia caused by vasa vasorum disorders. Disturbances in HDL acceptor function and transport of cholesterol and modified LDL to blood circulation and further into liver are followed by local accumulation of these products in smooth muscle cells. Overloaded by lipids smooth muscle cells move through internal fenestrated membrane thus activating receptor mechanism for transmission of modified lipoproteins to monocytes and capture of endothelial membrane and amorphous lipids by them in local lipid peroxidation area. A framework for hypothesis experimental and clinical testing is suggested.

Effect of impaired vasa vasorum flow on the structure and mechanics of the thoracic aorta: implications for the pathogenesis of aortic dissection.

OBJECTIVE: To investigate the alterations of structure and mechanical properties of the aortic wall, resulting from impairment of vasa vasorum flow. METHODS: Eight healthy Landrace pigs were subjected to interruption of vasa vasorum flow to the upper segment of their descending thoracic aorta. Under sterile conditions, the periaortic tissue was excised and the contiguous intercostal arteries were ligated. Ten sham-operated pigs were used as controls. Fifteen days postoperatively, the animals were sacrificed and their upper descending thoracic aortas were removed. Histology, and collagen and elastin content determination by image analysis technique were performed. Mechanical analysis of aortic strips was carried out with a uniaxial tension device and stress-strain curves were obtained. RESULTS: In contrast to normal aortic walls of the control group, histology of the avascular aortas revealed severe ischemic necrosis of the outer media along with abnormal straightening of the elastin and collagen fibers, without significant collagen and elastin content changes. The borderline between the outer ischemic and inner non-ischemic media was sharp, and an outset of dissection was observed at this point. Mechanical analysis showed that at the same level of strain, the ischemic aorta was significantly stiffer at both low (P=0.03) and high strains (P=0. 003). CONCLUSIONS: Impairment of blood supply to the thoracic aorta leads to abnormal morphology of elastin and collagen fibers of the outer media, resulting in increased aortic stiffness under a wide range of stresses. In the clinical setting, decreased vasa vasorum flow, reportedly occurring in arterial hypertension, may increase the stiffness of the outer media of the thoracic aorta and produce interlaminar shear stresses, contributing to the development of aortic dissection.