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Blood vessels have long been considered as passive conduits for blood and circulating cells that, at best, respond to exogenous cytokines. However, recent work has shown that blood vessels serve as a highly dynamic interface between the circulation and tissues. Augustin et al. review molecular mechanisms of vascular development and function in different organs. Differentiated endothelial cells develop as a sort of cobblestone monolayer to form one of the largest surfaces within the body. Vascular control of the tissue microenvironment is vital, not only for normal tissue development and homeostasis, but also for disease states ranging from inflammation to cancer. Science , this issue p. eaal2379 Blood vessels form one of the body’s largest surfaces, serving as a critical interface between the circulation and the different organ environments. They thereby exert gatekeeper functions on tissue homeostasis and adaptation to pathologic challenge. Vascular control of the tissue microenvironment is indispensable in development, hemostasis, inflammation, and metabolism, as well as in cancer and metastasis. This multitude of vascular functions is mediated by organ-specifically differentiated endothelial cells (ECs), whose cellular and molecular heterogeneity has long been recognized. Yet distinct organotypic functional attributes and the molecular mechanisms controlling EC differentiation and vascular bed–specific functions have only become known in recent years. Considering the involvement of vascular dysfunction in numerous chronic and life-threatening diseases, a better molecular understanding of organotypic vasculatures may pave the way toward novel angiotargeted treatments to cure hitherto intractable diseases. This Review summarizes recent progress in the understanding of organotypic vascular differentiation and function.

Patients with large abdominal aortic aneurysms were assigned to undergo endovascular repair or open surgical repair. Operative mortality was lower with endovascular repair, but at a median of 6 years, there was no significant difference between groups in total mortality or aneurysm-related mortality. There were more graft-related complications and reinterventions with endovascular repair. Patients with large abdominal aortic aneurysms were assigned to undergo either endovascular repair or open surgical repair. Operative mortality was lower with endovascular repair, but at a median of 6 years, there was no significant difference between groups in total mortality or aneurysm-related mortality. Abdominal aortic aneurysm is a common condition of increasing prevalence, particularly among older men. As the size of the aneurysm increases, so does the risk of rupture. Therefore, prophylactic repair with insertion of a prosthetic graft is offered. Since 1951, open surgical repair has been practiced. 1 Minimally invasive endovascular aneurysm repair was first reported in 1986. 2 The three principal randomized trials comparing endovascular and open repair of abdominal aortic aneurysm have all shown a marked benefit of endovascular repair with respect to 30-day operative mortality, 3 – 5 and these results have been supported by data from large registries. 6 Therefore, endovascular repair . . .

The mammalian skeletal system harbours a hierarchical system of mesenchymal stem cells, osteoprogenitors and osteoblasts sustaining lifelong bone formation. Osteogenesis is indispensable for the homeostatic renewal of bone as well as regenerative fracture healing, but these processes frequently decline in ageing organisms, leading to loss of bone mass and increased fracture incidence. Evidence indicates that the growth of blood vessels in bone and osteogenesis are coupled, but relatively little is known about the underlying cellular and molecular mechanisms. Here we identify a new capillary subtype in the murine skeletal system with distinct morphological, molecular and functional properties. These vessels are found in specific locations, mediate growth of the bone vasculature, generate distinct metabolic and molecular microenvironments, maintain perivascular osteoprogenitors and couple angiogenesis to osteogenesis. The abundance of these vessels and associated osteoprogenitors was strongly reduced in bone from aged animals, and pharmacological reversal of this decline allowed the restoration of bone mass. Bone homeostasis and repair declines with ageing and the mechanisms regulating the relationship between bone growth and blood vessel formation have remained unknown; this mouse study identifies the endothelial cells that promote the formation of new bone, a small microvessel subtype that can be identified by high CD31 and high Emcn expression. Bone growth and vascularization linked There is evidence to suggest that blood vessels, particularly their endothelial cells, control the growth, homeostasis and regeneration of organs. In two papers published in this issue of Nature , Ralf Adams and colleagues demonstrate that the bone vasculature contains endothelial cells specialized to support bone maturation and regeneration. Anjali Kusumbe et al . identify a capillary subtype in the mouse skeletal system that has a key role in mediating bone growth. These vessels contain so-called type H endothelial cells that preferentially associate with osteoprogenitors and are reduced during ageing. Hypoxia-inducible factor 1α (HIF-1α) is shown to be crucial in maintaining the type H cells, and the fact that these cells are lost in aged animals suggests that loss of HIF-1α signalling may be involved in age-related bone changes. In the second paper, Saravana Ramasamy et al . show that blood vessel growth in bone requires Notch signalling and involves a specialized form of angiogenesis that does not involve endothelial sprouts.

DNA origami-based nanorobot presents thrombin to cause tumor infarction after specific recognition of a tumor vessel marker. Nanoscale robots have potential as intelligent drug delivery systems that respond to molecular triggers 1 , 2 , 3 , 4 . Using DNA origami we constructed an autonomous DNA robot programmed to transport payloads and present them specifically in tumors. Our nanorobot is functionalized on the outside with a DNA aptamer that binds nucleolin, a protein specifically expressed on tumor-associated endothelial cells 5 , and the blood coagulation protease thrombin within its inner cavity. The nucleolin-targeting aptamer serves both as a targeting domain and as a molecular trigger for the mechanical opening of the DNA nanorobot. The thrombin inside is thus exposed and activates coagulation at the tumor site. Using tumor-bearing mouse models, we demonstrate that intravenously injected DNA nanorobots deliver thrombin specifically to tumor-associated blood vessels and induce intravascular thrombosis, resulting in tumor necrosis and inhibition of tumor growth. The nanorobot proved safe and immunologically inert in mice and Bama miniature pigs. Our data show that DNA nanorobots represent a promising strategy for precise drug delivery in cancer therapy.

Biodegradable scaffolds seeded with bone marrow mononuclear cells (BMCs) are the earliest tissue-engineered vascular grafts (TEVGs) to be used clinically. These TEVGs transform into living blood vessels in vivo, with an endothelial cell (EC) lining invested by smooth muscle cells (SMCs); however, the process by which this occurs is unclear. To test if the seeded BMCs differentiate into the mature vascular cells of the neovessel, we implanted an immunodeficient mouse recipient with human BMC (hBMC)-seeded scaffolds. As in humans, TEVGs implanted in a mouse host as venous interposition grafts gradually transformed into living blood vessels over a 6-month time course. Seeded hBMCs, however, were no longer detectable within a few days of implantation. Instead, scaffolds were initially repopulated by mouse monocytes and subsequently repopulated by mouse SMCs and ECs. Seeded BMCs secreted significant amounts of monocyte chemoattractant protein-1 and increased early monocyte recruitment. These findings suggest TEVGs transform into functional neovessels via an inflammatory process of vascular remodeling.

Adequate supply of blood and structural and functional integrity of blood vessels are key to normal brain functioning. On the other hand, cerebral blood flow shortfalls and blood–brain barrier dysfunction are early findings in neurodegenerative disorders in humans and animal models. Here we first examine molecular definition of cerebral blood vessels, as well as pathways regulating cerebral blood flow and blood–brain barrier integrity. Then we examine the role of cerebral blood flow and blood–brain barrier in the pathogenesis of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. We focus on Alzheimer’s disease as a platform of our analysis because more is known about neurovascular dysfunction in this disease than in other neurodegenerative disorders. Finally, we propose a hypothetical model of Alzheimer’s disease biomarkers to include brain vasculature as a factor contributing to the disease onset and progression, and we suggest a common pathway linking brain vascular contributions to neurodegeneration in multiple neurodegenerative disorders.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and a phenotypically similar recessive condition (CARASIL) have emerged as important genetic model diseases for studying the molecular pathomechanisms of cerebral small vessel disease (SVD). CADASIL, the most frequent and intensely explored monogenic SVD, is characterized by a severe pathology in the cerebral vasculature including the mutation-induced aggregation of the Notch3 extracellular domain (Notch3 ECD ) and the formation of protein deposits of insufficiently determined composition in vessel walls. To identify key molecules and pathways involved in this process, we quantitatively determined the brain vessel proteome from CADASIL patient and control autopsy samples ( n  = 6 for each group), obtaining 95 proteins with significantly increased abundance. Intriguingly, high-temperature requirement protein A1 (HTRA1), the extracellular protease mutated in CARASIL, was found to be strongly enriched (4.9-fold, p  = 1.6 × 10 −3 ) and to colocalize with Notch3 ECD deposits in patient vessels suggesting a sequestration process. Furthermore, the presence of increased levels of several HTRA1 substrates in the CADASIL proteome was compatible with their reduced degradation as consequence of a loss of HTRA1 activity. Indeed, a comparison with the brain vessel proteome of HTRA1 knockout mice ( n  = 5) revealed a highly significant overlap of 18 enriched proteins ( p  = 2.2 × 10 −16 ), primarily representing secreted and extracellular matrix factors. Several of them were shown to be processed by HTRA1 in an in   vitro proteolysis assay identifying them as novel substrates. Our study provides evidence for a loss of HTRA1 function as a critical step in the development of CADASIL pathology linking the molecular mechanisms of two distinct SVD forms.

Patients with large abdominal aortic aneurysms who were physically ineligible for open surgical repair were assigned to undergo endovascular repair or to receive no intervention. At a median of 3 years, aneurysm-related mortality was significantly lower with endovascular repair, but there was no difference in total mortality. Patients with large abdominal aortic aneurysms who were physically ineligible for open surgical repair were assigned to undergo endovascular repair or to receive no intervention. At a median of 3 years, aneurysm-related mortality was significantly lower with endovascular repair, but there was no difference in total mortality. Endovascular repair of abdominal aortic aneurysm was originally developed for patients who were considered to be physically ineligible for open surgical repair, 1 since it was thought that life expectancy would be prolonged by eliminating the risk of fatal rupture of an aneurysm. We designed the United Kingdom Endovascular Aneurysm Repair 2 (EVAR 2) trial to test this hypothesis. 2 The midterm results of the trial, reported in 2005, showed no benefit of endovascular repair on total or aneurysm-related mortality in up to 4 years of follow-up. 3 One factor underlying this unexpected result was an operative mortality rate that was higher than . . .

Interventions to restore blood vessel stability could improve health outcomes Not unlike Tolstoy's remark about happy versus unhappy families, current wisdom in vascular biology holds that healthy blood vessels are mostly similar, whereas vessels in different vascular diseases are mostly different. But is this really the case? An evaluation of the literature suggests that unresolved vascular remodeling may be a key element of virtually all vascular diseases. This commonality raises the possibility of unifying principles that govern vascular remodeling and the possibility that methods to restore normal remodeling could effectively treat multiple disease states.

Interferon-γ acts on tumour endothelial cells to drive vascular regression, inducing ischaemia that leads to tumour collapse. Tumour ischaemia by IFNγ Anti-tumour immune cells can elicit effects in tumours and stroma, but also in the blood vessels. Many of these effects are driven by secreted IFNγ, a cytokine with important functions in immunity. Using a combination of genetically engineered mouse models, the authors demonstrate that the effects of IFNγ on the vasculature is an important mediator of tumour clearance by the immune system. IFNγ-mediated tumour vascular remodelling resembles physiological processes, for example non-apoptotic blood vessel regression during wound healing, and induces early ischaemia that impairs the growth of tumour cells. The relative contribution of the effector molecules produced by T cells to tumour rejection is unclear, but interferon-γ (IFNγ) is critical in most of the analysed models 1 . Although IFNγ can impede tumour growth by acting directly on cancer cells 2 , 3 , it must also act on the tumour stroma for effective rejection of large, established tumours 4 , 5 . However, which stroma cells respond to IFNγ and by which mechanism IFNγ contributes to tumour rejection through stromal targeting have remained unknown. Here we use a model of IFNγ induction and an IFNγ–GFP fusion protein in large, vascularized tumours growing in mice that express the IFNγ receptor exclusively in defined cell types. Responsiveness to IFNγ by myeloid cells and other haematopoietic cells, including T cells or fibroblasts, was not sufficient for IFNγ-induced tumour regression, whereas responsiveness of endothelial cells to IFNγ was necessary and sufficient. Intravital microscopy revealed IFNγ-induced regression of the tumour vasculature, resulting in arrest of blood flow and subsequent collapse of tumours, similar to non-haemorrhagic necrosis in ischaemia and unlike haemorrhagic necrosis induced by tumour necrosis factor. The early events of IFNγ-induced tumour ischaemia resemble non-apoptotic blood vessel regression during development, wound healing or IFNγ-mediated, pregnancy-induced remodelling of uterine arteries 6 , 7 , 8 . A better mechanistic understanding of how solid tumours are rejected may aid the design of more effective protocols for adoptive T-cell therapy.