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Pulmonary arterial hypertension (PAH) is characterized by a progressive accumulation of pulmonary artery smooth muscle cells (PA-SMCs) in pulmonary arterioles leading to the narrowing of the lumen, right heart failure, and death. Although most studies have supported the notion of a role for IL-6/glycoprotein 130 (gp130) signaling in PAH, it remains unclear how this signaling pathway determines the progression of the disease. Here, we identify ectopic upregulation of membrane-bound IL-6 receptor (IL6R) on PA-SMCs in PAH patients and in rodent models of pulmonary hypertension (PH) and demonstrate its key role for PA-SMC accumulation in vitro and in vivo. Using Sm22a-Cre Il6rfl/fl, which lack Il6r in SM22A-expressing cells, we found that these animals are protected against chronic hypoxia-induced PH with reduced PA-SMC accumulation, revealing the potent pro-survival potential of membrane-bound IL6R. Moreover, we determine that treatment with IL6R-specific antagonist reverses experimental PH in two rat models. This therapeutic strategy holds promise for future clinical studies in PAH.

Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. Here, we describe aspects of the unique architecture of brain arterioles, histomorphologic features of B-ASC, relevant neuroimaging findings, epidemiology and association with aging, established genetic risk factors, and the co-occurrence of B-ASC with other neuropathologic conditions such as Alzheimer’s disease and limbic-predominant age-related TDP-43 encephalopathy (LATE). There may also be complex physiologic interactions between metabolic syndrome (e.g., hypertension and inflammation) and brain arteriolar pathology. Although there is no universally applied diagnostic methodology, several classification schemes and neuroimaging techniques are used to diagnose and categorize cerebral small vessel disease pathologies that include B-ASC, microinfarcts, microbleeds, lacunar infarcts, and cerebral amyloid angiopathy (CAA). In clinical-pathologic studies that factored in comorbid diseases, B-ASC was independently associated with impairments of global cognition, episodic memory, working memory, and perceptual speed, and has been linked to autonomic dysfunction and motor symptoms including parkinsonism. We conclude by discussing critical knowledge gaps related to B-ASC and suggest that there are probably subcategories of B-ASC that differ in pathogenesis. Observed in over 80% of autopsied individuals beyond 80 years of age, B-ASC is a complex and under-studied contributor to neurologic disability.

Cerebral small vessel disease (CSVD) represents a cluster of various vascular disorders with different pathological backgrounds. The advanced vasculature net of cerebral vessels, including small arteries, capillaries, arterioles and venules, is usually affected. Processes of oxidation underlie the pathology of CSVD, promoting the degenerative status of the epithelial layer. There are several classifications of cerebral small vessel diseases; some of them include diseases such as Binswanger’s disease, leukoaraiosis, cerebral microbleeds (CMBs) and lacunar strokes. This paper presents the characteristics of CSVD and the impact of the current knowledge of this topic on the diagnosis and treatment of patients.

Treatment of acute ischemic stroke with the thrombolytic tissue plasminogen activator (tPA) can significantly improve neurological outcomes; however, thrombolytic therapy is associated with an increased risk of intra-cerebral hemorrhage (ICH). Previously, we demonstrated that during stroke tPA acting on the parenchymal side of the neurovascular unit (NVU) can increase blood–brain barrier (BBB) permeability and ICH through activation of latent platelet-derived growth factor-CC (PDGF-CC) and signaling by the PDGF receptor-α (PDGFRα). However, in vitro, activation of PDGF-CC by tPA is very inefficient and the mechanism of PDGF-CC activation in the NVU is not known. Here, we show that the integrin Mac-1, expressed on brain microglia/macrophages (denoted microglia throughout), acts together with the endocytic receptor LRP1 in the NVU to promote tPA-mediated activation of PDGF-CC. Mac-1-deficient mice (Mac-1 −/− ) are protected from tPA-induced BBB permeability but not from permeability induced by intracerebroventricular injection of active PDGF-CC. Immunofluorescence analysis demonstrates that Mac-1, LRP1, and the PDGFRα all localize to the NVU of arterioles, and following middle cerebral artery occlusion (MCAO) Mac-1 −/− mice show significantly less PDGFRα phosphorylation, BBB permeability, and infarct volume compared to wild-type mice. Bone-marrow transplantation studies indicate that resident CD11b + cells, but not bone-marrow-derived leukocytes, mediate the early activation of PDGF-CC by tPA after MCAO. Finally, using a model of thrombotic stroke with late thrombolysis, we show that wild-type mice have an increased incidence of spontaneous ICH following thrombolysis with tPA 5 h after MCAO, whereas Mac-1 −/− mice are resistant to the development of ICH even with late tPA treatment. Together, these results indicate that Mac-1 and LRP1 act as co-factors for the activation of PDGF-CC by tPA in the NVU, and suggest a novel mechanism for tightly regulating PDGFRα signaling in the NVU and controlling BBB permeability.

We investigated the role of microRNAs (miRNA) in endothelial dysfunction in the setting of cardiometabolic disorders represented by type 2 diabetes mellitus (T2DM). miR‐29 was dysregulated in resistance arterioles obtained by biopsy in T2DM patients. Intraluminal delivery of miR‐29a‐3p or miR‐29b‐3p mimics restored normal endothelium‐dependent vasodilation (EDVD) in T2DM arterioles that otherwise exhibited impaired EDVD. Intraluminal delivery of anti‐miR‐29b‐3p in arterioles from non‐DM human subjects or rats or targeted mutation of Mir29b‐1/a gene in rats led to impaired EDVD and exacerbation of hypertension in the rats. miR‐29b‐3p mimic increased, while anti‐miR‐29b‐3p or Mir29b‐1/a gene mutation decreased, nitric oxide levels in arterioles. The mutation of Mir29b‐1/a gene led to preferential differential expression of genes related to nitric oxide including Lypla1. Lypla1 was a direct target of miR‐29 and could abrogate the effect of miR‐29 in promoting nitric oxide production. Treatment with Lypla1 siRNA improved EDVD in arterioles obtained from T2DM patients or Mir29b‐1/a mutant rats or treated with anti‐miR‐29b‐3p. These findings indicate miR‐29 is required for normal endothelial function in humans and animal models and has therapeutic potential for cardiometabolic disorders. Synopsis Administration of miR‐29 restores endothelium‐dependent vasodilation in arterioles from humans with cardiometabolic disorders, and endogenous miR‐29 is required for normal endothelial function in human and rat arterioles and blunts the development of hypertension in rats. microRNA expression profiles in resistance arterioles are altered in patients with cardiometabolic disorders represented by type 2 diabetes (T2DM). miR‐29 restores endothelium‐dependent vasodilation in resistance arterioles obtained from T2DM patients that otherwise exhibit endothelial dysfunction. miR‐29 is required for normal endothelial function in human and rat arterioles. miR‐29 insufficiencies exacerbate hypertension in rats. miR‐29 preferentially influenced the expression of genes relevant to the regulation of NO bioavailability in arterioles. Targeting of Lysophospholipase I (Lypla1) contributes to the effect of miR‐29 in promoting nitric oxide (NO) generation and endothelium‐dependent vasodilation. Graphical Abstract Administration of miR‐29 restores endothelium‐dependent vasodilation in arterioles from humans with cardiometabolic disorders, and endogenous miR‐29 is required for normal endothelial function in human and rat arterioles and blunts the development of hypertension in rats.

Modern functional imaging techniques of the brain measure local hemodynamic responses evoked by neuronal activity. Capillary pericytes recently were suggested to mediate neurovascular coupling in brain slices, but their role in vivo remains unexplored. We used two-photon microscopy to study in real time pericytes and the dynamic changes of capillary diameter and blood flow in the cortex of anesthetized mice, as well as in brain slices. The thromboxane A₂ analog, 9,11-dideoxy-9α, 11α-methanoepoxy Prostaglandin F2α (U46619), induced constrictions in the vicinity of pericytes in a fraction of capillaries, whereas others dilated. The changes in vessel diameter resulted in changes in capillary red blood cell (RBC) flow. In contrast, during brief epochs of seizure activity elicited by local administration of the GABA A receptor antagonist, bicuculline, capillary RBC flow increased without pericyte-induced capillary diameter changes. Precapillary arterioles were the smallest vessels to dilate, together with penetrating and pial arterioles. Our results provide in vivo evidence that pericytes can modulate capillary blood flow in the brain, which may be important under pathological conditions. However, our data suggest that precapillary and penetrating arterioles, rather than pericytes in capillaries, are responsible for the blood flow increase induced by neural activity.

Microcirculation contributes significantly to blood flow resistance, with upper airway microcirculation in obstructive sleep apnea (OSA) affected by endothelial activation, perturbed blood flow shear stress, and snoring-induced tissue vibration. The relevance of these mechanisms on microcirculation response and remodeling remains largely unknown but may influence management decisions in OSA. This study analyzed pharyngeal muscle tissue from non-obese, young adult patients with OSA and chronic heavy snoring. We assessed arteriole morphometry and quantified the expression of endothelial activation markers: 8-isoprostane, vascular cell adhesion molecule-1, E-selectin, vascular endothelial growth factor, endothelin-1, and endothelial cell specific molecule-1. Morphometric analysis of 319 arterioles (mean of 8 vessels per patient) revealed thicker walls in severe OSA compared to mild OSA without lumen reduction, indicating outward hypertrophy, and a positive correlation between the apnea–hypopnea index (a measure of OSA severity) and arteriole wall thickness. However, analysis of 1872 arterioles showed no increase in endothelial activation markers with disease severity, either in the arteriole walls or muscle tissue. This suggests that, in young non-obese adults, severe OSA likely leads to adaptive, mechanically driven microcirculation outward hypertrophy, potentially due to perturbed shear stress, with potential implications for OSA management.

Retinal vessel phenotype is predictive for cardiovascular outcome. This cross-sectional population-based study aimed to quantify normative data and standard operating procedures for static and dynamic retinal vessel analysis. We analysed central retinal arteriolar (CRAE) and venular (CRVE) diameter equivalents, as well as retinal endothelial function, measured by flicker light‐induced maximal arteriolar (aFID) and venular (vFID) dilatation. Measurements were performed in 277 healthy individuals aged 20 to 82 years of the COmPLETE study. The mean range from the youngest compared to the oldest decade was 196 ± 13 to 166 ± 17 µm for CRAE, 220 ± 15 to 199 ± 16 µm for CRVE, 3.74 ± 2.17 to 3.79 ± 2.43% for aFID and 4.64 ± 1.85 to 3.86 ± 1.56% for vFID. Lower CRAE [estimate (95% CI): − 0.52 (− 0.61 to − 0.43)], CRVE [− 0.33 (− 0.43 to − 0.24)] and vFID [− 0.01 (− 0.26 to − 0.00)], but not aFID, were significantly associated with older age. Interestingly, higher blood pressure was associated with narrower CRAE [− 0.82 (− 1.00 to − 0.63)] but higher aFID [0.05 (0.03 to 0.07)]. Likewise, narrower CRAE were associated with a higher predicted aFID [− 0.02 (− 0.37 to − 0.01)]. We recommend use of defined standardized operating procedures and cardiovascular risk stratification based on normative data to allow for clinical implementation of retinal vessel analysis in a personalized medicine approach.

Endothelial dysfunction comprises a number of functional alterations in the vascular endothelium that are associated with diabetes and cardiovascular disease, including changes in vasoregulation, enhanced generation of reactive oxygen intermediates, inflammatory activation, and altered barrier function. Hyperglycemia is a characteristic feature of type 1 and type 2 diabetes and plays a pivotal role in diabetes-associated microvascular complications. Although hyperglycemia also contributes to the occurrence and progression of macrovascular disease (the major cause of death in type 2 diabetes), other factors such as dyslipidemia, hyperinsulinemia, and adipose-tissue-derived factors play a more dominant role. A mutual interaction between these factors and endothelial dysfunction occurs during the progression of the disease. We pay special attention to the possible involvement of endoplasmic reticulum stress (ER stress) and the role of obesity and adipose-derived adipokines as contributors to endothelial dysfunction in type 2 diabetes. The close interaction of adipocytes of perivascular adipose tissue with arteries and arterioles facilitates the exposure of their endothelial cells to adipokines, particularly if inflammation activates the adipose tissue and thus affects vasoregulation and capillary recruitment in skeletal muscle. Hence, an initial dysfunction of endothelial cells underlies metabolic and vascular alterations that contribute to the development of type 2 diabetes.

Hypertension, aging, and other factors are associated with arteriosclerosis and arteriolosclerosis, primary morphological features of nephrosclerosis. Although such pathological changes are not invariably linked with renal decline but are prevalent across chronic kidney disease (CKD), understanding kidney damage progression is more pragmatic than precisely diagnosing nephrosclerosis itself. Hyalinosis and medial thickening of the afferent arteriole, along with intimal thickening of small arteries, can disrupt the autoregulatory system, jeopardizing glomerular perfusion pressure given systemic blood pressure (BP) fluctuations. Consequently, such vascular lesions cause glomerular damage by inducing glomerular hypertension and ischemia at the single nephron level. Thus, the interaction between systemic BP and afferent arteriolopathy markedly influences BP-dependent renal damage progression in nephrosclerosis. Both dilated and narrowed types of afferent arteriolopathy coexist throughout the kidney, with varying proportions among patients. Therefore, optimizing antihypertensive therapy to target either glomerular hypertension or ischemia is imperative. In recent years, clinical trials have indicated that combining renin–angiotensin system inhibitors (RASis) and sodium–glucose transporter 2 inhibitors (SGLT2is) is superior to using RASis alone in slowing renal function decline, despite comparable reductions in albuminuria. The superior efficacy of SGLT2is may arise from their beneficial effects on both glomerular hypertension and renal ischemia. A comprehensive understanding of the interaction between systemic BP and heterogeneous afferent arteriolopathy is pivotal for optimizing therapy and mitigating renal decline in patients with CKD of any etiology. Therefore, in this comprehensive review, we explore the role of afferent arteriolopathy in BP-dependent renal damage. Heterogeneous Afferent Arteriolopathy: A Key Concept for Optimizing Antihypertensive Therapy.