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Experimental angiogenesis of arterial vasa vasorum.

Vasa vasorum are important sources of oxygen and nutrients to vascular tissues and their proliferation influences the pathogenesis of arterial disease; however, the regulation of their growth is poorly understood partly because of a lack of appropriate experimental models. We cuffed common carotid arteries of rabbits with segments of the contralateral carotid artery, a procedure that resulted in rapid and extensive elaboration of adventitial vasa vasorum and connective tissue. Endothelium-lined microvessels were observed at 1 week but vessels as large as 300 microm with an organizing media were common by 3 weeks. These vasa vasorum arose primarily from the vascular supply to contiguous tissues, but also from the carotid artery. This angiogenesis was accompanied by increased expression of the angiogenic factor, vascular endothelial growth factor (VEGF), in the invading connective tissue cells and increased expression of the transcriptional regulator of VEGF, hypoxia-inducible factor-1alpha (HIF-1alpha), in these connective tissues and in the cuffing artery. These findings are consistent with the hypothesis that upregulation of HIF-1alpha and VEGF expression drives angiogenesis of vasa vasorum in this model. This simple model may be amenable to the study of the development and elaboration of vasa vasorum, especially in the context of vascular pathologies.

Animals↗

Pulmonary artery adventitial fibroblasts cooperate with vasa vasorum endothelial cells to regulate vasa vasorum neovascularization: a process mediated by hypoxia and endothelin-1.

The precise cellular and molecular mechanisms regulating adventitial vasa vasorum neovascularization, which occurs in the pulmonary arterial circulation in response to hypoxia, remain unknown. Here, using a technique to isolate and culture adventitial fibroblasts (AdvFBs) and vasa vasorum endothelial cells (VVECs) from the adventitia of pulmonary arteries, we report that hypoxia-activated pulmonary artery AdvFBs exhibited pro-angiogenic properties and influenced the angiogenic phenotype of VVEC, in a process of cell-cell communication involving endothelin-1 (ET-1). We demonstrated that AdvFBs, either via co-culture or conditioned media, stimulated VVEC proliferation and augmented the self-assembly and integrity of cord-like networks that formed when VVECs where cultured on Matrigel. In addition, hypoxia-activated AdvFBs produced ET-1, suggesting a paracrine role for this pro-angiogenic molecule in these processes. When co-cultured on Matrigel, AdvFBs and VVECs self-assembled into heterotypic cord-like networks, a process augmented by hypoxia but attenuated by either selective endothelin receptor antagonists or oligonucleotides targeting prepro-ET-1 mRNA. From these observations, we propose that hypoxia-activated AdvFBs exhibit pro-angiogenic properties and, as such, communicate with VVECs, in a process involving ET-1, to regulate vasa vasorum neovascularization occurring in the adventitia of pulmonary arteries in response to chronic hypoxia.

Animals↗

On the regulation of tone in vasa vasorum.

OBJECTIVE: The vasa vasorum form a network of microvessels in and around the walls of large blood vessels and are thought to be necessary to delivery oxygenated blood to the outer parts of the vessel wall that are inadequately nourished by diffusion from luminal blood. This study was undertaken to investigate directly the mechanisms which control tone in the vasa vasorum. METHODS: Arterial vasa vasorum were dissected from the walls of porcine or bovine thoracic aorta and mounted in a tension myograph. Concentration-response curves were constructed to vasoconstrictors; endothelin-1(ET-1), noradrenaline (NA) angiotensin II (Ang II) and thromboxane A2-mimetics (U44069 or U46619) or vasodilators; substance P (SP) bradykinin (BK), calcitonin gene-related peptide (CGRP) or isoprenaline. Strips of porcine aorta were mounted in 25 ml organ baths. RESULTS: Potent concentration-dependent contraction of vasa vasorum was produced by ET-1. NA was a weak constrictor, Ang II had no effect or produced contraction that underwent tachyphylaxis and thromboxane A2-mimetics had no effect. In contrast NA, Ang II, U-44069 and ET-1 all produced potent concentration-dependent contraction of aortic strips. SP and BK produced endothelium-dependent relaxation while CGRP produced endothelium-independent relaxation of ET-1-precontracted vasa vasorum. Isoprenaline had no relaxant effect. CONCLUSIONS: We have demonstrated functional responses of arterial vasa vasorum to vasodilators and vasoconstrictors. Additionally these microvessels appear to respond to constrictors differently from the large host vessel.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

Enhanced coronary vasa vasorum neovascularization in experimental hypercholesterolemia.

Coronary arteries contain a network of vasa vasorum in the adventitia. The three-dimensional anatomy of the vasa vasorum in early coronary atherosclerosis is unknown. This study was designed to visualize and quantitate the three-dimensional spatial pattern of vasa vasorum in normal and experimental hypercholesterolemic porcine coronary arteries, using a novel computed tomography technique. Animals were killed after being fed either a high cholesterol diet (n = 4) or a control diet (n = 4) for 12 wk. The proximal left anterior descending coronary artery was removed from the heart, scanned, and reconstructed, and quantitation of vasa vasorum density was performed. Two different types of vasa vasorum were defined: first-order vasa vasorum ran longitudinally parallel to the vessel and second-order originated from first-order vasa circumferentially around the vessel wall. Compared with controls in hypercholesterolemic coronary arteries, there was a significant increase in the area of the vessel wall (3.86+/-0.22 vs. 8.07+/-0.45 mm2, respectively, P < 0.01) and in the density of vasa vasorum (1. 84+/-0.05/mm2 vs. 4.73+/-0.24/mm2; respectively, P = 0.0001). This occurred especially by an increase of second-order vasa vasorum and disorientation of normal vasa vasorum spatial pattern. This study suggests that adventitial neovascularization of vasa vasorum occurs in experimental hypercholesterolemic coronary arteries and may be a part of the early atherosclerotic remodeling process.

Animals↗

Impact of coronary vasa vasorum functional structure on coronary vessel wall perfusion distribution.

Noncoronary vasa vasorum have been described as networks of microvessels in the wall of arteries and veins. However, we have shown, using microcomputerized tomography (micro-CT) imaging methods, that porcine coronary vasa vasorum have a tree-like branching structure similar to the vasculature in general. In this study, we elucidate functional aspects of coronary vasa vasorum perfusion territories. Three pig hearts were injected with radiopaque Microfil via the coronary sinus to fill the left anterior descending coronary arteries (LADs) retrogradely at atmospheric pressure. In three other hearts, LADs were injected antegradely at 100-mmHg pressure via the left main carotid artery. Additionally, six LADs were injected in vivo with a suspension of 100- or 300-microm-diameter microspheres before harvesting of the hearts and injection of the LADs with Microfil. All harvested LADs were scanned intact with micro-CT (20 microm cubic voxels). The spatial density of vasa vasorum (no. of vasa/mm2) was measured in 20-microm-thick cross sections (at 0.4-mm intervals). Retrogradely injected LADs showed high and uniformly distributed vasa vasorum densities in the adventitia (means +/- SE; 5.38 +/- 0.09 vs. 3.58 +/- 0.1 vasa/mm2 in antegradely prepared LADs; P < 0.001). Antegradely prepared LADs showed patchy distributed, low-vasa-vasorum-density territories especially on the myocardial side of the coronary artery wall (epicardial density: 4.29 +/- 0.13 vasa/mm2 vs. myocardial density: 2.80 +/- 0.1 vasa/mm2, P < 0.001). Microembolization reduced vasa vasorum densities significantly (100-mum-diameter microspheres: 3.26 +/- 0.07 vasa/mm2, P < 0.05; 300-microm-diameter microspheres: 2.66 +/- 0.07 vasa/mm2, P < 0.001 vs. antegrade controls) and increased the size of low-vasa-vasorum-density territories. We conclude that coronary vasa vasorum are functional endarteries not connected via a plexus. This characteristic may have a significant impact on the spatial distribution of perfusion and drainage of the coronary vessel wall.

Animals↗

Vasa vasorum of the intracranial arteries.

Most of the major extracranial arteries have vasa vasorum which play an important role in some pathological conditions. However, in the intracranial arteries, the existence of vasa vasorum and their pathological implication have not been adequately investigated. We examined the distribution and incidence of vasa vasorum in the major cerebral arteries and their relationships to certain clinical factors in 50 autopsy cases performed between 1987 and 1994. By light microscopy, vasa vasorum were found in 36 of 50 patients. Of 36 patients, vasa vasorum in 30 cases were localizedly observed in the tunica adventitia and the in other 6 were distributed in the tunica media accompanied by intramural haemorrhage. Existence of vasa vasorum was more common in the proximal arteries (vertebral, internal carotid, and basilar arteries) than in the distal arteries (middle cerebral and anterior cerebral arteries). Vasa vasorum were found more frequently in aged patients with severe atherosclerosis and those with cerebrovascular diseases. Our results indicated that intracranial vasa vasorum existed with a higher frequency in the tunica adventitia of the vertebral and internal cerebral arteries, and the incidence of vasa vasorum related to severity of atherosclerosis. The development of vasa vasorum in the tunica media may reflect some pathological changes of cerebral arteries.

Adolescent↗

The vasa vasorum and angioplasty.

Interruption of flow in the vasa vasorum may lead to medial necrosis and aneurysm formation. The purpose of this study was to determine whether angioplasty produces significant alterations in the morphology or blood flow of the vasa vasorum of the dilated artery. The morphology of the canine vasa vasorum was studied before and after angioplasty; in a separate experiment vessel wall blood flow (VWBF) in canine carotid arteries was measured after angioplasty to determine whether physiologic regulation of the blood flow was disrupted by arterial dilation. No morphologic changes could be demonstrated in the vasa vasorum of the dilated artery; however, VWBF was increased by 1194 +/- 215% (mean +/- standard error, p less than 0.01) between 90 and 120 minutes after angioplasty. VWBF in the adjacent nondilated arterial segment was also increased (720 +/- 177% between 10-30 minutes, p less than 0.01) but returned toward normal after 60 minutes. Adenosine caused a "paradoxical" decrease in VWBF (p less than 0.05) of the dilated arterial segment while causing increased VWBF (p less than 0.05) in the thoracic aorta. Angioplasty appears to produce persistent hyperemia in the dilated arterial wall. A paradoxical response to adenosine suggests that vasa vasorum in the dilated arterial segment are maximally vasodilated. This may be due to mechanical disruption of vasomotor tone or to release of vasoactive substances.

Adenosine↗

Role of vasa vasorum in nourishment of the aortic wall.

Vasa vasorum are present in the middle and outer layers of media in the thoracic aorta of dogs and humans. To examine the role of vasa vasorum in nourishment of the aorta, we ligated four contiguous pairs of intercostal arteries in anesthetized dogs. These arteries are the source of vasa to the descending aorta but not the aortic arch. Blood flow through vasa vasorum was measured with microspheres. Acute intercostal ligation did not reduce conductance in the aortic arch but reduced conductance in the middle third of the descending aorta from 7 +/- 1 to 3 +/- 0.7 (SE) ml.min-1.100 g-1.mmHg-1 (P less than 0.05). After intercostal ligation, infusion of adenosine (5 mumol.kg-1.min-1 iv) increased conductance in the aortic arch 3- to 4-fold but did not increase conductance in the descending aorta. Six to ten days after intercostal ligation, conductance in the middle third of the descending aorta remained low. Vasodilator capacity was partially restored in outer layers of the descending aorta, probably by collateral vessels or formation of new vessels. Morphological changes ranged from broad bands of necrosis to patchy areas of cell loss, primarily in middle layers of descending aorta. We conclude that vasa vasorum are critical in nourishment of aortic media.

Adenosine↗

Endogenous factors involved in regulation of tone of arterial vasa vasorum: implications for conduit vessel physiology.

The walls of conduit blood vessels are nourished by diffusion of oxygen from luminal blood and from the vasa vasorum. The vasa vasorum, or 'vessels of a vessel', 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 vasa vasorum in providing nutritional support is not well defined, obstruction of blood flow through these vessels has been implicated in the pathogenesis of certain cardiovascular diseases including atherosclerosis. This review focuses on the mechanisms that regulate tone in the vasa vasorum of large arteries and the functional implications of changes in reactivity of vasa vasorum.

Animals↗

Functional anatomy and hemodynamic characteristics of vasa vasorum in the walls of porcine coronary arteries.

In this study vasa vasorum in the walls of porcine coronary arteries were examined, using three-dimensional (3D) micro-CT scanning techniques. These techniques leave the 3D structure of the vasa vasorum tree intact and thus provide a much more direct view of this structure than is possible from conventional histological sections. The study demonstrates-for the first time, we believe-both the different types and the fine architecture of these vasa vasorum. Furthermore, with the use of automated tree analysis software, it was possible to obtain quantitative geometrical data on the 3D structure of vasa vasorum trees that have not previously been available. The results indicate that despite the restrictive topology of the space in which they are present, the branching architecture of the vasa vasorum trees, which we surveyed, is surprisingly similar to that of vasculature in general. The volume of vessel wall tissue perfused or drained by a vasa vasorum tree was found to correlate well with the cross-sectional area of the root segment of the vasa vasorum tree, and the luminal surface area corresponding to this volume was found to be comparable with the surface area of an early atherosclerotic lesion. This is consistent with earlier findings that the ligation or removal of vasa vasorum leads to atherogenesis.

Animals↗

[Modeling of elastic deformation and vascular resistance of arterial and venous vasa vasorum].

As in most living tissues, a network of nutritional vessels, the so-called vasa vasorum, irrigates the vessel wall under physiological conditions. An alteration or obstruction of this network can induce severe lesions. Most normal arteries and veins are irrigated by a vasa vasorum network located mainly in the adventice. They essentially supply oxygen to the outer layers of the vascular wall, the inner layer being mainly oxygenated by direct diffusion from bloodstream. Vasa vasorum responds to vasomotor stimuli and can even regress, e.g., after vascularization of arterial grafts. Their pathophysiological importance for arteries is now established. Indeed, it is known that an infusion disorder or vasa vasorum alteration may induce or promote early atherosclerotic lesions, fibrodysplasia or even media necrosis. From a mechanical point of view, and considering the three layers as a unique material, the vessel shows non-isotropic linear elastic and incompressible (v = 0.5) behaviour in the case of minimal or moderate deformation. But in the case of major deformation, the vessel displays a non-linear behaviour. The interaction between vasa vasorum supply and the mechanical properties of the arterial vascular wall can promote the occurrence of aneurysms as soon as vasa vasorum irrigation decreases. Some authors have hypothesized that these microvessels could fulfil the same function in the venous wall. It appears also that microcirculation flow rates are lower in varicose veins than in healthy ones and that partial oxygen pressure, already low in a healthy vein media, is even lower in a varicose vein. All these facts underline the importance of supply by the vasa vasorum network and its determining role in maintaining vascular wall integrity. In addition, the influence of vessel non-linear properties and their pathological changes on microcirculation would partially explain media necrosis in arteries and veins. Studying vascular wall deformation under the influence of intraluminal pressure revealed that an initially circular vasa vasorum rapidly takes on an elliptical shape which results more from crosswise circumferential stretching of the wall than from radial crushing. This induces increased hydraulic resistance. Thus permanent overpressure reduces vascular wall irrigation. Once the wall has been devascularized, it will loose its elasticity, harden and retain its maximal deformation. A vicious circle is then created. This phenomenon, noticeable in arteries, could be more serious in veins because their walls are thinner and elasticity modulus is lower. For example, for an intraluminal overpressure of 100 mmHg in an artery and 10 mmHg in a vein the ellipticity of the vasa vasorum becomes 1.2 and 3 respectively. Based on the hypothesis of a linear elastic behaviour and a periodical intraluminal overpressure, the ratio of the two axis of an arterial vasa vasorum B/A varies from 1.13 to 1.28 for Pa = 100 + 30 sin (2 pi t) mmHg, and from 1.24 to 1.44 for Pa = 160 + 40 sin (2 pi t) mmHg. In this case, the ratio of hydraulic resistances R(ellipse)/R(circle) changes little (less than 1, the ratio of the axis varies from 1.1 to 2.6 for Pa = 5 + 5 sin (2 pi t) mmHg) and from 1.8 to 5.8 for Pa = 10 + 5 sin (2 pi t) mmHg). Thus the ratio of hydraulic resistance varies from 1 to 1.5 and from 1.2 to 2.8 respectively. In practice Young's modulus increases in parallel with luminal pressure by limiting vascular wall and vasa vasorum deformation. If we consider the non-linear behaviour of the vessel wall and suppose the same conditions of intraluminal pressure, the ratio of the axis of the venous vasa vasorum in a hypertensive patient varies from 1.6 to 2.6 (instead of 1.8 to 5.8 in the case of linear model). This ratio is higher than that of the healthy subject which is less than 1.7. So the vascular structure in physiological conditions itself reacts to the pressure increases which may jeopardize vasa vasorum irrigation by delaying mural transfor

Animals↗

[The vasa vasorum in the veins of the spermatic cord].

Vasa vasorum is a vascular ensemble with nutritional role for the vascular wall. It's has the origin and the end at the surface of the bloods vessels. In the thickness of the external and internal tunics it represents by a capillary circulatory network. At the level of the adventitia of the veins, arterial vessels and vessels with a larger size, with a similar structure with the veins, has been observed. At the level of the middle tunic was observed capillary vasa vasorum. The density of the capillaries is bigger to the external tunic and the capillaries are in a smaller number to the internal tunic. The vascular wall has an intense metabolism, so we can explain the nutrient supply with two sources: an external source (vasa vasorum) and an internal source (the blood that flows in the vessels). The spermatic veins collect the blood from the testis, epididymis and the scrotum. This veins form a network around the arteries with a known functional role. This intimate vascular relation from the spermatic cord explains the arterial vasa vasorum particularities moreover the venous particularities. The drainage of the testicular veins is different on the left side and on the right side. The discussions are centered on the tension of the vascular wall. Its growth has an important effect: the compression of the capillary vasa vasorum. We discuss, too, about the conditions that reduce the perfusion. The consequence of an insufficient nutritional supply is the functional modification illustrated by varicocele.

Arteries↗

Effects of chronic hypertension on vasa vasorum in the thoracic aorta.

The outer layers of the thoracic aorta receive substantial blood flow through vasa vasorum within the aortic wall. Flow delivered via these channels is functionally important because medial necrosis occurs when vasa vasorum are ligated. If flow through vasa vasorum is limited in chronic hypertension, this could contribute to medial necrosis and, perhaps, aortic dissection. In these experiments, flow and conductance in vasa vasorum were assessed in twelve awake dogs with renal hypertension (arterial pressure = 127 +/- 4 mmHg [mean +/- SE]) and nine normotensive controls (arterial pressure = 100 +/- 3 mmHg [P less than 0.001]). At rest, blood flow delivered via vasa vasorum to the thoracic aorta was similar in hypertensive and normotensive dogs (5.2 +/- 0.9 and 4.8 +/- 0.4 ml . min-1 X 100 g-1 respectively). Thus, in hypertensive dogs, conductance of the vasa vasorum decreased to maintain flow constant. During maximal dilatation induced by iv adenosine (4.7 mumol . kg-1 per min) flow delivered via vasa vasorum increased by 100% in both hypertensive and normotensive dogs. Calculations of maximum conductance indicate that vasodilator capacity was decreased by 67% in vasa vasorum of hypertensive dogs. These data suggest that vasodilator capacity of vasa vasorum in the thoracic aorta is limited in chronic hypertension. This abnormality could contribute to the pathogenesis of medial necrosis and aortic dissection in hypertensive patients.

Adenosine↗

Revascularization of occluded internal carotid arteries by hypertrophied vasa vasorum: report of four cases.

OBJECTIVE AND IMPORTANCE: The vasa vasorum are involved in the pathophysiological development of carotid artery atherosclerosis, providing vascular support to the thickened intima and plaque. When advanced atherosclerosis causes carotid artery occlusion, the vasa vasorum may serve as a means of revascularization. CLINICAL PRESENTATION: We studied four patients with internal carotid artery occlusion who exhibited revascularization, distal to the occlusion, by small vascular channels that were inconsistent with recanalization through the thrombus. The channels had an angiographic appearance consistent with their being hypertrophied vasa vasorum. Significant collateral circulation was provided by the revascularization. INTERVENTION: All four patients exhibited adequate collateral circulation and were treated with antiplatelet or anticoagulation medication. CONCLUSION: The vasa vasorum have not been previously reported to contribute to the revascularization of occluded arteries. The four cases presented in this report suggest that the vasa vasorum can be a source of collateral circulation after carotid artery occlusion secondary to atherosclerotic disease.

Aged↗

Do human intracranial arteries lack vasa vasorum? A comparative immunohistochemical study of intracranial and systemic arteries.

Vasa vasorum are adventitial vessels that play a role in pathogenesis of atherosclerosis, aneurysm, vasculitides, and graft vascular disease. The existence of vasa vasorum in human intracranial arteries is not yet well defined. The specific aims of this study are to determine whether the human intracranial arteries have vasa vasorum, whether their existence is related to the thickness of tunica media as is in systemic vessels, and whether they are acquired in reaction to pathological conditions, such as atherosclerosis and arterial occlusion. Human intracranial internal carotid (i-ICA), vertebral (i-VA), basilar (BA) and middle cerebral arteries (MCA) from adults, children and newborns were examined. Systemic vessels of comparable medial thickness were used as controls. Immunohistochemical staining for Factor VIII and CD 31 was used to identify the endothelial cells. Human intracranial arteries in neonates, children and adults do not have vasa vasorum, although their medial thickness is comparable to their systemic counterparts with vasa vasorum. Only in adults did the proximal intracranial segments of i-ICA and i-VA reveal a few vasa vasorum-like vessels with unusually large diameter. They were more frequently seen in atherosclerosis and thrombotic but again limited to the proximal segments of i-ICA and i-VA. Completely obstructed bilateral carotid arteries in a child with sickle cell disorder revealed a rich adventitial neovascularization in the proximal intracranial part of the vessel. It is not yet known whether obstruction of the distal segments may create similar neovascularizations. Adventitial neovascularizations seen in the proximal i-ICA and i-VA may represent a focal intracranial extension of the vascular pathologies involving the extracranial segments of major cerebral arteries.

Adolescent↗

Effect of vasa vasorum flow on structure and function of the aorta in experimental animals.

BACKGROUND: It is known that vasa vasorum flow contributes substantially to the nutrition of the outer layers of the thoracic aorta. This investigation was undertaken to test the hypothesis that impairment of vasa vasorum flow would alter the structure of the aortic wall and change the elastic properties of the aorta. METHODS AND RESULTS: The periaortic fat that contain the vasa vasorum for the ascending aorta was removed in seven anesthetized dogs, and the results were compared with those obtained from six weight-matched sham-operated control dogs. Aortic pressures, aortic diameters, and aortic distensibility were obtained before and 30 minutes and 15 days after removal of the periaortic vasa vasorum network. Aortic pressures were measured directly with a fluid-filled catheter. Aortic diameters were measured simultaneously with aortic pressures with an elastic, air-filled ring connected to a transducer. Aortic distensibility was calculated by the formula 2 x pulsatile change in aortic diameter/(diastolic aortic diameter x pulse pressure). Histology was performed in transverse blocks of aortic wall at the end of the experiment in both groups. The efficacy of the technique for the interruption of vasa vasorum blood supply to the aortic wall was demonstrated by histology in four additional animals that were killed without removal of vasa vasorum (two animals) and immediately after vasa vasorum removal (two animals). At baseline, heart rate, aortic pressures, aortic diameters, and aortic distensibility were similar in the two groups. A significant decrease in aortic distensibility was observed 30 minutes and 15 days after removal of the vasa vasorum in the experimental group (baseline, 3.453 +/- 1.023; 30 minutes, 2.521 +/- 0.760; 15 days, 1.586 +/- 0.488 10(-6).cm2.dyn-1; F = 9.532, P < .001). No changes were observed in aortic distensibility in the control group during the experiment. Histology of the aorta revealed medial necrosis, alterations of the elastin fibers, and a trend (P = .055) for altered collagen-to-elastin ratio in a region occupying more than the one (outer) half of the media of the experimental group animals. No changes were observed in the control group. CONCLUSIONS: The findings of the present study demonstrated that interruption of vasa vasorum flow led to an acute decrease in the distensibility of the ascending aorta. Moreover, structural changes of the aortic wall and further deterioration of the elastic properties of the aorta occurred 15 days after vasa vasorum removal.

Animals↗

Hypoxia-inducible factor-1alpha/vascular endothelial growth factor pathway for adventitial vasa vasorum formation in hypertensive rat aorta.

The roles of adventitial vasa vasorum have been highlighted in vascular wall homeostasis. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor in physiological and pathophysiological conditions. However, little is known regarding the changes in adventitial vasa vasorum and the mechanism of the formation in hypertensive arteries. Accordingly, endothelial cell proliferation, adventitial vasa vasorum count, and expression of VEGF signaling axis proteins were examined in the ascending aorta of hypertensive Wistar rats that underwent suprarenal aortic constriction. Hypertension not only induced medial and adventitial thickening but also significantly increased adventitial vasa vasorum count by day 28. Preceding the medial thickening, BrdU(+)-proliferative endothelial cells were observed in the adventitia but not in the media and intima after day 3; they peaked at day 7 and remained modestly increased at day 28. The BrdU(+) endothelial cells showed induction of Ets-1, a transcription factor mediating angiogenic response of VEGF. Furthermore, concomitant expression of VEGF and a hypoxia-inducible transcription factor (HIF-1alpha) was observed in the outer layers of medial smooth muscle cells at day 3 and extended to the middle layers of medial smooth muscle cells at day 7, returning to lower levels by day 28. In conclusion, adventitial vasa vasorum formation was induced by hypertension through the HIF-1alpha/VEGF/Ets-1 pathway during hypertensive remodeling.

Animals↗