Central nervous system diseases involving the parenchymal microvessels are frequently associated with a ‘microvasculopathy’, which includes different levels of neurovascular unit (NVU) dysfunction, including blood–brain barrier alterations. To contribute to the understanding of NVU responses to pathological noxae, we have focused on one of its cellular components, the microvascular pericytes, highlighting unique features of brain pericytes with the aid of the analyses carried out during vascularization of human developing neocortex and in human gliomas. Thanks to their position, centred within the endothelial/glial partition of the vessel basal lamina and therefore inserted between endothelial cells and the perivascular and vessel-associated components (astrocytes, oligodendrocyte precursor cells (OPCs)/NG2-glia, microglia, macrophages, nerve terminals), pericytes fulfil a central role within the microvessel NVU. Indeed, at this critical site, pericytes have a number of direct and extracellular matrix molecule- and soluble factor-mediated functions, displaying marked phenotypical and functional heterogeneity and carrying out multitasking services. This pericytes heterogeneity is primarily linked to their position in specific tissue and organ microenvironments and, most importantly, to their ontogeny. During ontogenesis, pericyte subtypes belong to two main embryonic germ layers, mesoderm and (neuro)ectoderm, and are therefore expected to be found in organs ontogenetically different, nonetheless, pericytes of different origin may converge and colonize neighbouring areas of the same organ/apparatus. Here, we provide a brief overview of the unusual roles played by forebrain pericytes in the processes of angiogenesis and barriergenesis by virtue of their origin from midbrain neural crest stem cells. A better knowledge of the ontogenetic subpopulations may support the understanding of specific interactions and mechanisms involved in pericyte function/dysfunction, including normal and pathological angiogenesis, thereby offering an alternative perspective on cell subtype-specific therapeutic approaches.

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Neural crest cell-derived pericytes act as pro-angiogenic cells in human neocortex development and gliomas

The coronavirus disease 2019 (COVID-19) pandemic has rapidly transformed the whole world and forced us to look through comorbid diseases and risk factors from a different perspective. COVID-19 shows some inherent risk factors like cardiovascular comorbidities independent from age, gender, and geographic location. One of the most peculiar features of the COVID-19 pandemic is that severe acute respiratory syndrome coronavirus 2 respiratory infections disproportionately impact patients with hypertension, diabetes, and other cardiovascular comorbidities rather than those with allergic respiratory diseases and immune-compromised conditions. Migraine is a complex neuro-vasculo-inflammatory disorder that is also packed frequently with certain medical conditions including vascular disorders, hypertension, allergic diseases such as asthma and systemic inflammatory disorders. Accordingly, 2 different questions arise during the pandemic: (1) Do share comorbidities of cardiovascular diseases and hypertension increase the risk of symptomatic COVID-19 for migraine patients? (2) Do comorbid allergic and atopic diseases, including asthma act as opposite influencers alongside with female gender? This paper focuses on the co-existence of comorbidities of COVID-19, in comparison with migraine, based on a wide clinical dataset and available reports. Discussed mechanisms include potential strategic roles of angiotensin-converting enzyme 2, angiotensin-II, and nucleotide oligomerization domain-like receptor family, pyrin domain containing 3 inflammasome, playing remarkable parts in the pathogenesis of COVID-19 and migraine. There are also some clues about the importance of endothelial and pericyte dysfunction and neuroinflammation in COVID-19 infection, related to complications and survival of the patients. The large epidemiological studies as well as basic research, focusing on migraine patients with COVID-19 will clarify these vital questions during the upcoming periods.

Are Migraine Patients at Increased Risk for Symptomatic Coronavirus Disease 2019 Due to Shared Comorbidities

Alzheimer's disease (AD) is clinically characterized by a progressive loss of cognitive functions and short-term memory. AD patients present two distinctive neuropathological lesions: neuritic plaques and neurofibrillary tangles (NFTs), constituted of beta-amyloid peptide (Aβ) and phosphorylated and truncated tau proteins. Aβ deposits around cerebral blood vessels (cerebral amyloid angiopathy, CAA) is a major contributor to vascular dysfunction in AD. Vascular amyloid deposits could be early events in AD due to dysfunction in the neurovascular unit (NVU) and the blood-brain barrier (BBB), deterioration of the gliovascular unit, and/or decrease of cerebral blood flow (CBF). These pathological events can lead to decreased Aβ clearance, facilitate a neuroinflammatory environment as well as synaptic dysfunction and, finally, lead to neurodegeneration. Here, we review the histopathological AD hallmarks and discuss the two-hit vascular hypothesis of AD, emphasizing the role of neurovascular dysfunction as an early factor that favors vascular Aβ aggregation and neurodegeneration. Addtionally, we emphasize that pericyte degeneration is a key and early element in AD that can trigger amyloid vascular accumulation and NVU/BBB dysfunction. Further research is required to better understand the early pathophysiological mechanisms associated with NVU alteration and CAA to generate early biomarkers and timely treatments for AD.

Neurovascular dysfunction and vascular amyloid accumulation as early events in Alzheimer's disease

Pericytes facilitate blood–brain barrier (BBB) integrity; however, the mechanisms involved remain unclear. Hence, using co-cultures of human cerebral microvascular endothelial cells (ECs) and vascular pericytes (PCs) in different spatial arrangements, as well as PC conditioned media, we investigated the impact of PC-EC orientation and PC-derived soluble factors on EC barrier function. We provide the first evidence that barrier-inducing properties of PCs require basolateral contact with ECs. Gene expression analysis (GEA) in ECs co-cultured with PCs versus ECs alone showed significant upregulation of 38 genes and downregulation of 122 genes. Pathway enrichment analysis of modulated genes showed significant regulation of several pathways, including transforming growth factor-β and interleukin-1 regulated extracellular matrix, interferon and interleukin signaling, immune system signaling, receptor of advanced glycation end products (RAGE), and cytokine–cytokine receptor interaction. Transcriptomic analysis showed a reduction in molecules such as pro-inflammatory cytokines and chemokines, which are known to be induced during BBB disruption. Moreover, cytokine proteome array confirmed the downregulation of key pro-inflammatory cytokines and chemokines on the protein level. Other molecules which influence BBB and were favorably modulated upon EC-PC co-culture include IL-18 binding protein, kallikrein-3, CSF2 CSF3, CXCL10, CXCL11 (downregulated) and IL-1-R4; HGF, PDGF-AB/BB, PECAM, SERPIN E1 (upregulated). In conclusion, we provide the first evidence that (1) basolateral contact between ECs and PCs is essential for EC barrier function and integrity; (2) in ECs co-cultured with PCs, the profile of BBB disrupting pro-inflammatory molecules and cytokines/chemokines is downregulated; (3) PCs significantly modulate EC mechanisms known to improve barrier function, including TGF-β regulated ECM pathway, anti-inflammatory cytokines, growth factors and matrix proteins. This human PC-EC co-culture may serve as a viable in vitro model for investigating BBB function and drug transport.

https://www.zora.uzh.ch/id/eprint/206494/1/Kurmann_et_al_cells-10-00963.pdf

Transcryptomic Analysis of Human Brain-Microvascular Endothelial Response to -Pericytes: Cell Orientation Defines Barrier Function

Ovarian steroid-regulated cyclical regeneration of the endometrium is crucial for endometrial receptivity and embryo implantation, and it is dependent on the dynamic remodeling of the endometrial vasculature. Perivascular cells, including pericytes surrounding capillaries and microvessels and adventitial cells located in the outermost layer of large vessels, show properties of mesenchymal stem cells, and they are thus promising candidates for uterine regeneration. In this review, we discuss the structure and functions of the endometrial blood vasculature and their roles in endometrial regeneration, the main biomarkers and characteristics of perivascular cells in the endometrium, and stem cell-based angiogenetic therapy for Asherman’s syndrome.

https://www.mdpi.com/2075-4426/11/6/477/pdf

Endometrial Perivascular Progenitor Cells and Uterus Regeneration.

Pericyte, a kind of pluripotent cell, may regulate the irrigation flow and permeability of microcirculation Pericytes are similar to the smooth muscle cells, which express several kinds of contractile proteins and have contractility The dysfunction of pericytes is related to many microvascular diseases, including hypoxia, hypertension, diabetic retinopathy, fibrosis, inflammation, Alzheimer's disease, multiple sclerosis, and tumor formation For a long time, their existence and function have been neglected The distribution, structure, biomarker, related signaling pathways as well as the roles of pericytes on vascular diseases will be introduced in this review

Research advances in pericyte function and their roles in diseases.

Background Sepsis is a major cause of death in ICU, and intestinal barrier dysfunction is its important complication, while the treatment is limited. Recently, mesenchymal stem cell-derived microvesicles (MMVs) attract much attention as a strategy of cell-free treatment; whether MMVs are therapeutic in sepsis induced-intestinal barrier dysfunction is obscure. Methods In this study, cecal ligation and puncture-induced sepsis rats and lipopolysaccharide-stimulated intestinal epithelial cells to investigate the effect of MMVs on intestinal barrier dysfunction. MMVs were harvested from mesenchymal stem cells and were injected into sepsis rats, and the intestinal barrier function was measured. Afterward, MMVs were incubated with intestinal epithelial cells, and the effect of MMVs on mitochondrial dynamic balance was measured. Then the expression of mfn1, mfn2, OPA1, and PGC-1α in MMVs were measured by western blot. By upregulation and downregulation of mfn2 and PGC-1α, the role of MMVs in mitochondrial dynamic balance was investigated. Finally, the role of MMV-carried mitochondria in mitochondrial dynamic balance was investigated. Results MMVs restored the intestinal barrier function by improving mitochondrial dynamic balance and metabolism of mitochondria. Further study revealed that MMVs delivered mfn2 and PGC-1α to intestinal epithelial cells, and promoted mitochondrial fusion and biogenesis, thereby improving mitochondrial dynamic balance. Furthermore, MMVs delivered functional mitochondria to intestinal epithelial cells and enhanced energy metabolism directly. Conclusion MMVs can deliver mfn2, PGC-1α, and functional mitochondria to intestinal epithelial cells, synergistically improve mitochondrial dynamic balance of target cells after sepsis, and restore the mitochondrial function and intestinal barrier function. The study illustrated that MMVs might be a promising strategy for the treatment of sepsis.

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Mesenchymal stem cell-derived microvesicles improve intestinal barrier function by restoring mitochondrial dynamic balance in sepsis rats.

BACKGROUND It is well known that sepsis is a prevalent severe disease caused by infection and the treatment strategies are limited. Recently pericyte-derived microvesicles (PMVs) were confirmed to be therapeutic in many diseases, whether PMVs can protect vascular endothelial cell (VEC) injury is unknown. METHODS Pericytes were extracted from the retina of newly weaned rats, and PMVs were collected after starvation and characterized by flow-cytometry and transmission electron microscopy. First, the effect of PMVs on pulmonary vascular function in septic rats was measured via intravenous administration with HE staining, immunofluorescence, and Elisa analysis. Then, PMVs were co-incubated with VECs in the presence of lipopolysaccharide (LPS), and observed the protective effect of PMVs on VECs. Next, the proteomic analysis and further Gene Ontology (GO) enrichment analysis were performed to analyze the therapeutic mechanism of PMVs, and the angiogenesis-related protein CTGF was highly expressed in PMVs. Finally, by CTGF upregulation and downregulation in PMV, the role of PMV-carried CTGF was investigated. RESULTS PMVs restored the proliferation and angiogenesis ability of pulmonary VECs, and alleviated pulmonary vascular leakage in septic rats and LPS-stimulated VECs. Further study showed that PMVs delivered CTGF to VECs, and subsequently activated ERK1/2, and increased the phosphorylation of STAT3, thereby improving the function of VECs. The further study found CD44 mediated the absorption and internalization of PMVs to VECs, the anti-CD44 antibody inhibited the protective effect of PMVs. CONCLUSIONS PMVs may delivery CTGF to VECs, and promote the proliferation and angiogenesis ability by activating the CTGF-ERK1/2-STAT3 axis, thereby protecting pulmonary vascular function in sepsis. The therapeutic effect of PMVs was highly related to CD44-mediated absorption. Video Abstract.

The protective effects of pericyte-derived microvesicles on vascular endothelial functions via CTGF delivery in sepsis.

Vascular hyperpermeability is a complication of hemorrhagic shock. Pericytes (PCs) are a group of mural cells surrounded by microvessels that are located on the basolateral side of the endothelium. Previous studies have shown that damage to PCs contributes to the occurrence of many diseases such as diabetic retinopathy and myocardial infarction. Whether PCs can protect the vascular barrier function following hemorrhagic shock and the underlying mechanisms are unknown. A hemorrhagic shock rat model, Cx43 vascular endothelial cell (VEC)-specific knockdown mice, and VECs were used to investigate the role of PCs in vascular barrier function and their relationship with Cx43. The results showed that following hemorrhagic shock, the number of PCs in the microvessels was significantly decreased and was negatively associated with an increase in pulmonary and mesenteric vascular permeability. Exogenous infusion of PCs (106 cells per rat) colonized the microvessels and improved pulmonary and mesenteric vascular barrier function. Upregulation of Cx43 in PCs significantly increased the number of PCs colonizing the pulmonary vessels. In contrast, downregulation of Cx43 expression in PCs or knockout of Cx43 in VECs (Cx43 KO mice) significantly reduced PC colonization in pulmonary vessels in vivo and reduced direct contact formation between PCs and VECs in vitro. It has been suggested that PCs have an important protective effect on vascular barrier function in pulmonary and peripheral vessels following hemorrhagic shock. Cx43 plays an important role in the colonization of exogenous PCs in the microvessels. This finding provides a potential new shock treatment measure.

Henan Zhou

Papers

Research advances in pericyte function and their roles in diseases.

Mesenchymal stem cell-derived microvesicles improve intestinal barrier function by restoring mitochondrial dynamic balance in sepsis rats.

The protective effects of pericyte-derived microvesicles on vascular endothelial functions via CTGF delivery in sepsis.

The protective effect of pericytes on vascular permeability after hemorrhagic shock and their relationship with Cx43