c-Jun, Foxo3a, and c-Myc Transcription Factors are Key Regulators of ATP-Mediated Angiogenic Responses in Pulmonary Artery Vasa Vasorum Endothelial Cells.

Angiogenic vasa vasorum (VV) expansion plays an essential role in the pathogenesis of hypoxia-induced pulmonary hypertension (PH), a cardiovascular disease. We previously showed that extracellular ATP released under hypoxic conditions is an autocrine/paracrine, the angiogenic factor for pulmonary artery (PA) VV endothelial cells (VVECs), acting via P2Y purinergic receptors (P2YR) and the Phosphoinositide 3-kinase (PI3K)-Akt-Mammalian Target of Rapamycin (mTOR) signaling. To further elucidate the molecular mechanisms of ATP-mediated VV angiogenesis, we determined the profile of ATP-inducible transcription factors (TFs) in VVECs using a TranSignal protein/DNA array. C-Jun, c-Myc, and Foxo3 were found to be upregulated in most VVEC populations and formed nodes connecting several signaling networks. siRNA-mediated knockdown (KD) of these TFs revealed their critical role in ATP-induced VVEC angiogenic responses and the regulation of downstream targets involved in tissue remodeling, cell cycle control, expression of endothelial markers, cell adhesion, and junction proteins. Our results showed that c-Jun was required for the expression of ATP-stimulated angiogenic genes, c-Myc was repressive to anti-angiogenic genes, and Foxo3a predominantly controlled the expression of anti-apoptotic and junctional proteins. The findings from our study suggest that pharmacological targeting of the components of P2YR-PI3K-Akt-mTOR axis and specific TFs reduced ATP-mediated VVEC angiogenic response and may have a potential translational significance in attenuating pathological vascular remodeling.

The antiangiogenic activity of rPAI-1(23) inhibits vasa vasorum and growth of atherosclerotic plaque.

Plaque vascularity has been implicated in its growth and stability. However, there is a paucity of information regarding the origin of plaque vasculature and the role of vasa vasorum in plaque growth. To inhibit growth of vasa vasorum in atherogenic mice and assess its effect on plaque growth, we used a truncated plasminogen activator inhibitor (PAI)-1 protein, rPAI-1(23), that has significant antiangiogenic activity. Female LDLR(-/-)ApoB-48-deficient mice fed Paigen's diet without cholate for 20 weeks received rPAI-1(23) treatment (n=21) for the last 6 weeks. Plaque size and vasa vasorum density were compared to 2 controls: mice fed Paigen's diet and treated with saline for the last 6 weeks (n=16) and mice fed Paigen's diet until the onset of treatment (n=14). The rPAI-1(23) treatment significantly reduced plaque area and plaque cholesterol in the descending aorta and plaque area in the innominate artery. Measurements of reconstructed confocal microscopy images of vasa vasorum demonstrate that rPAI-1(23) treatment decreased vasa vasorum area and length, which was supported by microCT images. Confocal images provide evidence for vascularized plaque in the saline-treated group but not in rPAI-1(23)-treated mice. The increased vessel density in saline-treated mice is attributable, in part, to upregulated fibroblast growth factor-2 expression, which is inhibited by rPAI-1(23). In conclusion, rPAI-1(23) inhibits growth of vasa vasorum, as well as vessels within the adjacent plaque and vessel wall, through inhibition of fibroblast growth factor-2, leading to reduced plaque growth in atherogenic female LDLR(-/-)ApoB-48-deficient mice.

Vasa vasorum neovascularization and lesion distribution among different vascular beds in ApoE-/-/LDL-/- double knockout mice.

OBJECTIVE: To increase understanding of the substantial variation in the incidence and distribution of atherosclerotic lesions among different vascular beds. In view of some evidence that there are different distributions of adventitial vasa vasorum (VV) in different vascular beds, and that this correlates with lesion formation, we explored this possible linkage in apoE-/-/LDL-/- double knockout mice, which develop VV at age beyond 16 weeks. METHODS AND RESULTS: Samples from the aorta, coronary, pulmonary, carotid, and cerebral arteries in apoE-/-/LDL-/- double knockout mice at the age of 16-80 weeks (n=24) were scanned by micro-CT. Using those 3D images, we characterized plaque volume, vessel luminal diameter and VV luminal volume along the vessels. Results were complemented by histology. Advanced atherosclerotic lesions were found in the aorta, pulmonary artery and carotid artery. Occluded intramyocardial vessels (vessel diameter approximately 0.1mm) with concomitant myocardial infarctions were found without any evidence of adventitial VV neovascularization. VV luminal volume follows the order: aorta>pulmonary arteries>carotid arteries. VV were only observed in atherosclerotic diseased vessels with a lumen diameter>0.4mm. No atherosclerotic lesions, and no VV, were observed in cerebral arteries. CONCLUSION: The spatial heterogeneity in the development of atherosclerotic lesions among different vascular beds is linked to appearance of VV and to vessel lumen diameter.

Vasa vasorum growth in the coronary arteries of newborn pigs.

Experimental studies have shown that a "plexus" of vasa vasorum already exists in fetal arteries. In this study we examine the further development of vasa vasorum in the newborn. Hearts from 1- and 6-month-old pigs were harvested and infused with Microfil via the aortic ostia of the coronary arteries at physiological pressure (100 mmHg). Coronary arteries (RCA, LAD, and LCX) were then isolated and scanned intact with micro-CT (20 microm cubic voxel size). Using Analyze 5.0 software we digitally isolated individual vasa vasorum trees (eight from 1-month-old and eight from 6-month-old pigs) and measured geometrical data such as interbranch segmental diameters, lengths, and branching angles as well as mother-daughter branch relationships for all segments of each vasa vasorum tree structure. Also, we determined the volume of vessel wall perfused by individual vasa vasorum trees. Our results show that the vasa vasorum architecture in newborn pigs is already tree-like, and this structure as well as the volume of vessel wall perfused by it expand in concert with the growth of the host coronary artery. We give quantitative details of this growth of vasa vasorum in terms of its branching architecture and hemodynamic capacity, based on direct measurements from 3D images of this microvasculature.

Age-related alterations in the morphology of femoral artery vasa vasorum in the rat.

The objective of this study was to explore any age-related morphological changes in the vasa vasorum of the rat femoral artery. Vascular corrosion casts were prepared from 2, 12 and 24-month-old rats. Examination of the casts with the scanning electron microscope revealed dramatic differences in the appearance of the vessels of young and aged rats. The vasa vasorum of 2-month-old rats consisted of a dense network of capillaries. These vessels were dramatically reduced in number by 12 months, and even fewer capillaries were present at 24 months. This reduction in capillary density is consistent with the observed age-related decreases in oxygen tension and may explain why the aged are more prone to atherosclerosis.

The development of vasa vasorum of the human aorta in various conditions. A morphometric study.

The developmental behavior of vasa vasorum under various conditions was studied on the wall tissues of aorta and great arteries from 29 autopsy cases, where the length density (LA) of vasa vasorum in a unit area of wall was determined by morphometry. In a control group, LA was found to increase exponentially, along with increasing wall thickness D, among arteries from various anatomic sites of patients with greatly divergent ages. The regression curve crossed the x-axis at D = 0.6 mm, showing that arteries thicker than this have an auxiliary circulation by vasa vasorum. The LA was markedly high both in neonates and in patients with cyanotic heart anomaly, ie, in conditions where medial cells were sustained under reduced oxygen supply. Thus, vasa vasorum were shown to elongate their intramural segments in response to the changes of microenvironment in which the medial cells are placed, meeting the demand by the cells for increased supply of oxygen and nutrients.

[Age and variability in the blood vessels of the walls of the human iliac veins]. / Vozrastnaia izmenchivost' krovenosnykh sosudov stenok podvzdoshnykh ven cheloveka.

The investigation of the vascular bed in walls of the human iliac veins has been performed in 92 preparations obtained from embryos, children and mature persons of both sex by means of injection and non-injection methods. It has been stated that vascular bed in walls of the human iliac veins includes the intramural vessels both delivering and evacuating blood. Structural changes of the intramural bed in ontogenesis can be followed during three stages (development and differentiation, stabilization, involution).