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Many conditions affecting the heart, brain, and even the eyes have their origins in blood vessel pathology, underscoring the role of vascular regulation. In age-related macular degeneration (AMD), there is excessive growth of abnormal blood vessels in the eye (choroidal neovascularization), eventually leading to vision loss due to detachment of retinal pigmented epithelium. As the advanced stage of this disease involves loss of retinal pigmented epithelium, much less attention has been given to early vascular events such as endothelial dysfunction. Although current gold standard therapy using inhibitors of vascular endothelial growth factor (VEGF) have achieved initial successes, some drawbacks include the lack of long-term restoration of visual acuity, as well as a subset of the patients being refractory to existing treatment, alluding us and others to hypothesize upon VEGF-independent mechanisms. Against this backdrop, we present here a nonexhaustive review on the vascular underpinnings of AMD, implications with genetic and systemic factors, experimental models for studying choroidal neovascularization, and interestingly, on both endothelial-centric pathways and noncell autonomous mechanisms. We hope to shed light on future research directions in improving vascular function in ocular disorders.

Vascular smooth muscle cells (SMCs) arise from diverse developmental origins. Regional distribution of vascular diseases may, in part, be attributed to this inherent heterogeneity in SMC lineage. Therefore, systems for generating human SMC subtypes of distinct embryonic origins would represent useful platforms for studying the influence of SMC lineage on the spatial specificity of vascular disease. Here we describe how human pluripotent stem cells can be differentiated into distinct populations of SMC subtypes under chemically defined conditions. The initial stage (days 0–5 or 0–7) begins with the induction of three intermediate lineages: neuroectoderm, lateral plate mesoderm and paraxial mesoderm. Subsequently, these precursor lineages are differentiated into contractile SMCs (days 5–19+). At key stages, the emergence of lineage-specific markers confirms recapitulation of embryonic developmental pathways and generation of functionally distinct SMC subtypes. The ability to derive an unlimited supply of human SMCs will accelerate applications in regenerative medicine and disease modeling.

Numerous reports of vascular events after an initial recovery from COVID-19 form our impetus to investigate the impact of COVID-19 on vascular health of recovered patients. We found elevated levels of circulating endothelial cells (CECs), a biomarker of vascular injury, in COVID-19 convalescents compared to healthy controls. In particular, those with pre-existing conditions (e.g., hypertension, diabetes) had more pronounced endothelial activation hallmarks than non-COVID-19 patients with matched cardiovascular risk. Several proinflammatory and activated T lymphocyte-associated cytokines sustained from acute infection to recovery phase, which correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Notably, we found higher frequency of effector T cells in our COVID-19 convalescents compared to healthy controls. The activation markers detected on CECs mapped to counter receptors found primarily on cytotoxic CD8 + T cells, raising the possibility of cytotoxic effector cells targeting activated endothelial cells. Clinical trials in preventive therapy for post-COVID-19 vascular complications may be needed.

Vascular dementia is the second most common form of dementia. Yet, the mechanisms by which cerebrovascular damage progresses are insufficiently understood. Here, we create bilateral common carotid artery stenosis in mice, which effectively impairs blood flow to the brain, a major cause of the disease. Through imaging and single-cell transcriptomics of the mouse cortex, we uncover that blood vessel venous cells undergo maladaptive structural changes associated with increased Epas1 expression and activation of developmental angiogenic pathways. In a human cell model comparing arterial and venous cells, we observe that low-oxygen condition leads to sustained EPAS1 signaling specifically in venous cells. EPAS1 inhibition reduces cerebrovascular abnormalities, microglial activation, and improves markers of cerebral perfusion in vivo. In human subjects, levels of damaged endothelial cells from venous vessels are correlated with white matter injury in the brain and poorer cognitive functions. Together, these findings indicate EPAS1 as a potential therapeutic target to restore cerebrovascular integrity and mitigate neuroinflammation. How changes in brain blood vessels lead to a chronic reduction in blood flow and, consequently, to vascular dementia is poorly understood. Here, the authors show that venous endothelial dysfunction driven by EPAS1 promotes abnormal vascular remodeling and contributes to cognitive decline.

Background Polypoidal choroidal vasculopathy (PCV), a subtype of age-related macular degeneration (AMD), is a global leading cause of vision loss in older populations. Distinct from typical AMD, PCV is characterized by polyp-like dilatation of blood vessels and turbulent blood flow in the choroid of the eye. Gold standard anti-vascular endothelial growth factor (anti-VEGF) therapy often fails to regress polypoidal lesions in patients. Current animal models have also been hampered by their inability to recapitulate such vascular lesions. These underscore the need to identify VEGF-independent pathways in PCV pathogenesis. Results We cultivated blood outgrowth endothelial cells (BOECs) from PCV patients and normal controls to serve as our experimental disease models. When BOECs were exposed to heterogeneous flow, single-cell transcriptomic analysis revealed that PCV BOECs preferentially adopted migratory-angiogenic cell state, while normal BOECs undertook proinflammatory cell state. PCV BOECs also had a repressed protective response to flow stress by demonstrating lower mitochondrial functions. We uncovered that elevated hyaluronidase-1 in PCV BOECs led to increased degradation of hyaluronan, a major component of glycocalyx that interfaces between flow stress and vascular endothelium. Notably, knockdown of hyaluronidase-1 in PCV BOEC improved mechanosensitivity, as demonstrated by a significant 1.5-fold upregulation of Krüppel-like factor 2 ( KLF2 ) expression, a flow-responsive transcription factor. Activation of KLF2 might in turn modulate PCV BOEC migration. Barrier permeability due to glycocalyx impairment in PCV BOECs was also reversed by hyaluronidase-1 knockdown. Correspondingly, hyaluronidase-1 was detected in PCV patient vitreous humor and plasma samples. Conclusions Hyaluronidase-1 inhibition could be a potential therapeutic modality in preserving glycocalyx integrity and endothelial stability in ocular diseases with vascular origin.

[...]other phenotypes such as inner mitochondrial membrane (IMM) hyperpolarization could not be recapitulated. [...]there is a need to better understand the contribution of BMPR2 mutations to PAH-associated phenotypes and the requirement for other factors in this process. Derivation of iPSC-SMCs and iPSC-ECs that perfectly represent adult PASMCs and PAECs is yet to be achieved. [...]our goal was to generate iPSC-SMCs that recapitulated some of the important functional responses of adult-derived distal PASMCs, as well as iPSCECs with enhanced expression of arterial markers, that could be used as surrogates for adult pulmonary vascular cells. [...]these protocols will have a broad effect for those modeling pulmonary vascular diseases, and also for those using pulmonary organoids and pulmonary artery-on-chip technologies to study epithelial-endothelial cell interactions in the alveoli and for drug screening. [...]this study defines an iPSC-derived SMC model of PAH.

Myocardin is thought to have a key role in smooth muscle cell (SMC) development by acting on CArG-dependent genes. However, it is unclear whether myocardin-induced SMC maturation and increases in agonist-induced calcium signalling are also associated with increases in the expression of non-CArG-dependent SMC-specific genes. Moreover, it is unknown whether myocardin promotes SMC development from human embryonic stem cells. Findings The effects of adenoviral-mediated myocardin overexpression on SMC development in human ESC-derived embryoid bodies were investigated using immunofluorescence, flow cytometry and real time RT-PCR. Myocardin overexpression from day 10 to day 28 of embryoid body differentiation increased the number of smooth muscle α-actin(+) and smooth muscle myosin heavy chain(+) SMC-like cells and increased carbachol-induced contractile function. However, myocardin was found to selectively regulate only CArG-dependent SMC-specific genes. Nevertheless, myocardin expression appeared to be sufficient to specify the SMC lineage. Myocardin increases the development and maturation of SMC-like cells from human embryonic stem cells despite not activating the full repertoire of SMC genes. These findings have implications for vascular tissue engineering and other applications requiring large numbers of functional SMCs.

Background SARS-CoV-2, the causative agent of COVID-19, is a threat to public health. Evidence suggests increased neutrophil activation and endothelial glycocalyx (EG) damage are independently associated with severe COVID-19. Here, we hypothesised that an increased level of blood neutrophil myeloperoxidase (MPO) is associated with soluble EG breakdown, and inhibiting MPO activity may reduce EG damage. Methods Analysing a subset of acute and convalescent COVID-19 plasma, 10 from severe and 15 from non-severe COVID-19 cases, and 9 from pre-COVID-19 controls, we determined MPO levels, MPO activity and soluble EG proteins (syndecan-1 and glypican-1) levels by enzyme-linked immunosorbent assay. In vitro primary human aortic endothelial cells were cultured with plasma untreated or treated with specific MPO inhibitors (MPO-IN-28, AZD5904) to determine EG shedding. We then investigated whether inhibiting MPO activity decreased EG degradation. Results In COVID-19 plasma, MPO levels, MPO activity and levels of soluble EG proteins are significantly raised compared to controls, and concentrations increase in proportion to disease severity. Despite clinical recovery, protein concentrations remain significantly elevated. Interestingly, there is a trend of increasing MPO activity in convalescent plasma in both severe and non-severe groups. MPO levels and MPO activity correlate significantly with soluble EG levels and inhibiting MPO activity leads to reduced syndecan-1 shedding, in vitro. Conclusions Neutrophil MPO may increase EG shedding in COVID-19, and inhibiting MPO activity may protect against EG degradation. Further research is needed to evaluate the utility of MPO inhibitors as potential therapeutics against severe COVID-19. Plain language summary COVID-19 can result in severe disease and is potentially fatal. Neutrophils, the most abundant white blood cells in circulation, secrete antimicrobials that have been linked to severe COVID-19 development. The endothelial glycocalyx (EG) is a carbohydrate rich layer that coats the inner surface of the vasculature and damage to the EG is observed in severe COVID-19. Here, we investigate whether myeloperoxidase, an antimicrobial released by neutrophils, is associated with EG damage in COVID-19 patients. We also determine whether reducing myeloperoxidase activity prevents damage to the EG. Our results suggest myeloperoxidase is associated with EG damage and severe COVID-19. We also demonstrated that a reduction in myeloperoxidase activity may protect against EG degradation. Further studies to evaluate the utility of MPO inhibitors as a therapy against severe COVID-19 are warranted. Teo et al. study neutrophil activity and endothelial glycocalyx damage in plasma collected from healthy individuals and patients with severe and non-severe COVID-19. They show that neutrophil myeloperoxidase activity and endothelial glycocalyx proteins increase with disease severity, and remain high despite clinical recovery.

The chicken embryo is widely used as an experimental model in the areas of regenerative medicine, tumor biology, and angiogenesis. Eggshell opacity and rigidity present restricted three‐dimensional (3D) viewing and accessibility to the embryo and its circulatory network despite egg windowing. The ability to engineer an eggshell, which eliminates the opacity yet provides 3D access for manipulation is beneficial and would potentially make it enticing for the use of chicken embryo as a cheaper alternative vertebrate model. Here, we present the feasibility of fabricating a morphologically analogous transparent chicken eggshell made of polydimethylsiloxane using a biaxial rotation computer‐controlled bioreactor to achieve uniform thickness. By culturing chicken embryo in the bioengineered eggshell, we demonstrated success in meeting developmental milestones and its practicality as an experimental platform by visualizing both embryo and vasculature development using common laboratory imaging tools. Although the viability of the embryo in the bioengineered eggshell was lower than in the normal egg, this was attributed to the absence of calcium source. The bioengineered eggshell, in its initial stage of development, provides a platform to be used to investigate beyond gross observations of the embryo and vascular network in 3D optical clarity and its imaging capabilities has the potential to be extended to other imaging modalities. We have developed a transparent ex ovo eggshell, biomimicking the elliptical geometry to address the lack of 3D optical clarity contributed by the eggshell opacity. This retains the natural shape that may support the development of the chicken embryo and allows easy access to the embryo, its circulatory system and respective organ development in far reaching applications. We have created a transparent bioengineered eggshell for chicken embryo experimentations, and demonstrated the capabilities of this ex ovo culture set‐up for live visualization of embryonic development. This platform could have far reaching applications in the fields of regenerative medicine, drug testing and angiogenesis.

The endothelium is pivotal in multiple physiological processes, such as maintaining vascular homeostasis, metabolism, platelet function, and oxidative stress. Emerging evidence in the past decade highlighted the immunomodulatory function of endothelium, serving as a link between innate, adaptive immunity and inflammation. This review examines the regulation of the immune–inflammatory axis by the endothelium, discusses physiological immune functions, and explores pathophysiological processes leading to endothelial dysfunction in various metabolic disturbances, including hyperglycemia, obesity, hypertension, and dyslipidaemia. The final section focuses on the novel, repurposed, and emerging therapeutic targets that address the immune–inflammatory axis in endothelial dysfunction.