Vascular Remodeling: Just Say NO!

“You are only as old as your endothelium”, as often stated by Paul M Vanhoutte, when opening his famous “Mechanisms of Vasodilation” meetings from 1980 onwards, highlights the importance of endothelium and the continuous process of vascular remodeling in many physiological and pathophysiological situations as embryogenesis, wound healing, tumor growth and ischemic disease. In chronic and acute cardiovascular occlusive disease, different types of vascular remodeling contribute to tissue repair and vascular growth. Firstly, collateral growth represents the expansive growth of preexisting vessels, forming collateral bridges between arterial networks. Secondly, neovascularization refers to vascular growth from a combination of three different mechanisms: vasculogenesis is the formation of blood vessels by endothelial progenitors while angiogenesis refers to capillary sprouting or intussusceptive growth and arteriogenesis to the subsequent stabilization of these new vascular structures by mural cells1. Distinct, but partially overlapping, cellular and molecular pathways drive collateral growth and neovascularization (Figure 1)2. Hypoxia is known to stimulate neovascularization in the setting of ischemia, whereas fluid shear stress (FSS) might be the most important trigger for initiation of collateral growth. Besides these specific initial triggers, all types of vascular remodeling share growth factors, chemokines, proteases, and inflammatory cells, which play different roles in promoting and refining these processes

Multicenter experience of upper extremity access in complex endovascular aortic aneurysm repair

Purpose: Upper extremity access (UEA) for antegrade cannulation of aortic side branches is a relevant part of endovascular treatment of complex aortic aneurysms and can be achieved using several techniques, sites, and sides. The purpose of this study was to evaluate different UEA strategies in a multicenter registry of complex endovascular aortic aneurysm repair (EVAR). Methods: In six aortic centers in the Netherlands, all endovascular aortic procedures from 2006 to 2019 were retrospectively reviewed. Patients who received UEA during complex EVAR were included. The primary outcome was a composite end point of any access complication, excluding minor hematomas. Secondary outcomes were access characteristics, access complications considered individually, access reinterventions, and incidence of ischemic cerebrovascular events. Results: A total of 417 patients underwent 437 UEA for 303 fenestrated/branched EVARs and 114 chimney EVARs. Twenty patients had bilateral, 295 left-sided, and 102 right-sided UEA. A total of 413 approaches were performed surgically and 24 percutaneously. Distal brachial access (DBA) was used in 89 cases, medial brachial access (MBA) in 149, proximal brachial access (PBA) in 140, and axillary access (AA) in 59 cases. No significant differences regarding the composite end point of access complications were seen (DBA: 11.3% vs MBA: 6.7% vs PBA: 13.6% vs AA: 10.2%; P =.29). Postoperative neuropathy occurred most after PBA (DBA: 1.1% vs MBA: 1.3% vs PBA: 9.3% vs AA: 5.1%; P =.003). There were no differences in cerebrovascular complications between access sides (right: 5.9% vs left: 4.1% vs bilateral: 5%; P =.75). Significantly more overall access complications were seen after a percutaneous approach (29.2% vs 6.8%; P =.002). In multivariate analysis, the risk for access complications after an open approach was decreased by male sex (odds ratio [OR]: 0.27; 95% confidence interval [CI]: 0.10-0.72; P =.009), whereas an increase in age per year (OR: 1.08; 95% CI: 1.004-1.179; P =.039) and diabetes mellitus type 2 (OR: 3.70; 95% CI: 1.20-11.41; P =.023) increased the risk. Conclusions: Between the four access localizations, there were no differences in overall access complications. Female sex, diabetes mellitus type 2, and aging increased the risk for access complications after a surgical approach. Furthermore, a percutaneous UEA resulted in higher complication rates than a surgical approach

DEFICIENCY OF MYELOID PHD PROTEINS AGGRAVATES ATHEROGENESIS VIA MACROPHAGE APOPTOSIS AND PARACRINE FIBROTIC SIGNALING Atherogenic effects of myeloid PHD knockdown

AIMS: Atherosclerotic plaque hypoxia is detrimental for macrophage function. Prolyl hydroxylases (PHDs) initiate cellular hypoxic responses, possibly influencing macrophage function in plaque hypoxia. Thus, we aimed to elucidate the role of myeloid PHDs in atherosclerosis. METHODS AND RESULTS: Myeloid-specific PHD knockout (PHDko) mice were obtained via bone marrow transplantation (PHD1ko, PHD3ko) or conditional knockdown through lysozyme M-driven Cre recombinase (PHD2cko). Mice were fed high cholesterol diet for 6–12 weeks to induce atherosclerosis. Aortic root plaque size was significantly augmented 2.6-fold in PHD2cko, and 1.4-fold in PHD3ko compared to controls but was unchanged in PHD1ko mice. Macrophage apoptosis was promoted in PHD2cko and PHD3ko mice in vitro and in vivo, via the hypoxia-inducible factor (HIF) 1α/BNIP3 axis. Bulk and single-cell RNA data of PHD2cko bone marrow-derived macrophages (BMDMs) and plaque macrophages, respectively, showed enhanced HIF1α/BNIP3 signalling, which was validated in vitro by siRNA silencing. Human plaque BNIP3 mRNA was positively associated with plaque necrotic core size, suggesting similar pro-apoptotic effects in human. Furthermore, PHD2cko plaques displayed enhanced fibrosis, while macrophage collagen breakdown by matrix metalloproteinases, collagen production, and proliferation were unaltered. Instead, PHD2cko BMDMs enhanced fibroblast collagen secretion in a paracrine manner. In silico analysis of macrophage-fibroblast communication predicted SPP1 (osteopontin) signalling as regulator, which was corroborated by enhanced plaque SPP1 protein in vivo. Increased SPP1 mRNA expression upon PHD2cko was preferentially observed in foamy plaque macrophages expressing ‘triggering receptor expressed on myeloid cells-2’ (TREM2hi) evidenced by single-cell RNA, but not in neutrophils. This confirmed enhanced fibrotic signalling by PHD2cko macrophages to fibroblasts, in vitro as well as in vivo. CONCLUSION: Myeloid PHD2cko and PHD3ko enhanced atherosclerotic plaque growth and macrophage apoptosis, while PHD2cko macrophages further activated collagen secretion by fibroblasts in vitro, likely via paracrine SPP1 signalling through TREM2hi macrophages

Reduction of blood pressure, plasma cholesterol, and atherosclerosis by elevated endothelial nitric oxide.

In the vascular system, nitric oxide is generated by endothelial NO synthase (eNOS). NO has pleiotropic effects, most of which are believed to be atheroprotective. Therefore, it has been argued that patients suffering from cardiovascular disease could benefit from an increase in eNOS activity. However, increased NO production can cause oxidative damage, cell toxicity, and apoptosis and hence could be atherogenic rather than beneficial. To study the in vivo effects of increased eNOS activity, we created transgenic mice overexpressing human eNOS. Aortic blood pressure was approximately 20 mm Hg lower in the transgenic mice compared with control mice because of lower systemic vascular resistance. The effects of eNOS overexpression on diet-induced atherosclerosis were studied in apolipoprotein E-deficient mice. Elevation of eNOS activity decreased blood pressure ( approximately 20 mm Hg) and plasma levels of cholesterol (approximately 17%), resulting in a reduction in atherosclerotic lesions by 40%. We conclude that an increase in eNOS activity is beneficial and provides protection against atherosclerosis