Pooneh Bagher

We systematically assessed vasoreactivity of multiple aortic regions in male and female wild-type mice via wire myography. We observed regional and sex differences in vasoreactivity along the aorta, suggesting that the mouse aorta is heterogeneous and not a uniform conduit vessel for blood distribution. Notably, the infrarenal aorta was unique in its vasomotor responses. These data serve as a reference for assay design of aortic function in disease states and highlight region-specific sex differences.

Space exploration is important for scientific discovery, advancing technology, and the long-term survival of humanity. However, the impacts of microgravity and cosmic radiation during space travel on human physiology are not completely understood. While microgravity results in a loss of skeletal muscle mass and function, the effect on cardiac muscle, in particular the contractile elements, is not as clear. Here, we examine the effect of spaceflight on the myocardial contractile function of skinned cardiomyocytes from mice that traveled to the International Space Station (spaceflight, N = 5) and age-matched ground controls (ground control, N = 5, and vivarium, N = 3). These experiments allow for the characterization of the mechanical properties of the sarcomere, the fundamental unit of contraction. The functional experiments showed that ~38.5 days in space does not alter force-generating capacity (T_max), calcium sensitivity (EC₅₀), and cooperativity of the sarcomere. The passive force and cross-sectional area (CSA) were the same between the spaceflight and ground control groups. We next performed mass spectrometry (MS) analysis, and gene ontology analysis confirmed that pathways associated with sarcomere contractility remained unchanged. However, the MS data showed that the spaceflight group exhibited immune‑related proteomic changes compared to the ground controls. Together, these results suggest that ~38.5 days of space travel does not substantially affect the intrinsic contractile state of murine cardiomyocytes.

Iron deficiency is a highly prevalent nutrient deficiency and the most common cause of anemia. Although iron deficiency exacerbates cardiovascular disease, the direct impact of iron deficiency on the vasculature remains unstudied. We assessed iron levels across the vascular endothelium in mouse and human endothelial cells and found resistance artery endothelial cells have the lowest iron stores, suggesting they may be especially impacted by iron deficiency. Anemia has previously been shown to increase arterial NO signaling in patients, and we have previously shown endothelial a-globin scavenges nitric oxide (NO) in the resistance artery endothelium. We hypothesized iron regulates vascular function through regulation of endothelial a-globin. To test this, we used a mouse model of iron deficiency anemia (IDA). In female mice, IDA increased NO signaling, which was rescued to control levels by repletion of vascular iron with iron dextran. Despite being similarly anemic and having a similar reduction in a-globin protein, there were no changes in NO signaling across groups in male mice. We further measured whether a-globin was in its heme-bound (holo a-globin) or heme-free (apo a-globin) state and found males did not fully lose its functional, heme-bound a-globin. Using endothelial specific a-globin knockout mice, we show loss of endothelial a-globin is necessary for increased NO signaling in IDA and for the rescue of NO signaling by iron dextran in female mice. Altogether, the data presented here demonstrate iron is a determinant of endothelial identity and modulates endothelial NO signaling through the regulation of a-globin.

The endothelium plays a central role in maintaining vascular homeostasis by orchestrating vascular tone, inflammation, healing, permeability, and thrombosis. Assessing endothelial function in vascular tissue is essential for understanding the cellular and molecular mechanisms underlying cardiovascular physiology and pathology. Traditional approaches, such as wire and pressure myography, have been instrumental in defining endothelium-dependent responses and identifying key pharmacological targets. However, the complexity and heterogeneity of endothelial cells across vascular beds and their dynamic phenotypic changes in health and disease necessitate the incorporation of new investigative strategies. Emerging methodologies, including bulk and single-cell transcriptomics, proteomics, and advanced imaging, now provide unprecedented insights into endothelial cell diversity and function. A team of leading experts in the field, who collectively reached a consensus on the most widely used techniques to evaluate endothelial function, developed these guidelines. The document establishes best practices for assessing endothelial function, from endothelial cell cultures to isolated vascular tissues, integrating conventional functional assays with modern molecular approaches. By fostering methodological consistency and embracing innovation, our goal is to enhance rigor, reproducibility, understanding, and discovery in endothelial biology.

Human space exploration is rapidly advancing, with long-term expeditions becoming more common. Long-term space missions introduce prolonged exposure to microgravity and ionizing radiation, which elicit stress responses throughout many organ systems. As the cerebrovascular system is responsible for regulating blood flow to the brain, it is imperative to understand the effects of the space environment on the cerebrovascular system. Cerebrovascular alterations are also linked to neurological diseases such as Alzheimer’s Disease, Parkinson’s Disease, glaucoma, and stroke. This systematic review evaluates the current literature to demonstrate that spaceflight conditions (actual or ground-based analogs) can lead to changes in the cerebrovascular system at the network, cellular, and molecular levels. These findings demonstrate differences and similarities between cerebrovascular alterations due to the space environment and neurological conditions, highlighting that the mechanisms behind the reversibility and readaptation to Earth following spaceflight could inform treatments of neurological disease.

Cardiometabolic syndrome (CMS) encompasses a cluster of metabolic abnormalities, including obesity, insulin resistance, dyslipidemia, and hypertension, that collectively increase the risk of cardiovascular disease and type 2 diabetes. Animal models are widely used to study CMS, with diet-induced models being the most physiologically relevant. A lack of reporting standards and variability in dietary composition, feeding duration, and macronutrient content across studies hinder reproducibility assessment and translational impact evaluation. We provide standardized guidelines for the consideration, preparation, and use of diets in experimental models of CMS. Advantages and limitations of different diet-induced models are compared with genetic and pharmacological approaches, emphasizing replicability to human metabolic dysregulation. Key components include macronutrient composition, fat source selection, feeding duration, strain susceptibility, and sex differences. In addition, we outline husbandry practices, including environmental factors, bedding material, and enrichment conditions, which can affect metabolic outcomes. Standardization is essential for enhancing experimental reproducibility and facilitating cross-study comparisons. These guidelines serve as a framework for researchers to optimize dietary interventions in CMS models, improving the predictive value of preclinical findings for translational applications to aid in the development of targeted therapeutic strategies.

It is with great sadness that we inform the Journal of Vascular Research community of the passing of Eva Aralikatti on May 19, 2024. Many of you would

Signaling across membranes is vital for tissue and organ function throughout the body. This is achieved through careful regulation of transmembrane channels allowing for passage of ions and second messengers to and from the cytosol and intracellular compartments, which can generate electrical impulses and trigger signaling cascades. Connexins and pannexins are among the most versatile transmembrane channel proteins, which shape cell behavior and tissue function with extraordinary finesse. In this volume, pannexins and connexins 37, 40, and 43 are reviewed [1‒4], with special consideration for tissue specificity of expression, cell type-specific functions, and their roles in development and disease.The term “connexin” first appeared in the literature in 1974 [5] and was named as such due to the ability of connexins to “connect” adjacent cells via a “nexus” (of the Latin origin “to bind”) [6]. The first connexin was not cloned until 1986 [7], but since then the field has rapidly expanded due to identification of 21 different human connexins with tissue-specific roles [8]. Of note, four connexin proteins (Cx): Cx37, Cx40, Cx43, and Cx45 are expressed and play a crucial functional role in blood vessels [2‒4]. Gap junctions form when six-connexin oligomers, collectively known as a hemichannel or connexon, bind with another hemichannel on an adjacent cell to make a single nonselective pore that crosses both plasma membranes [9]. It should be noted that connexin hemichannels function both individually and when coupled to an adjacent hemichannel to form a gap junction. Thus, gap junctions allow for physical and electrical coupling between adjacent cells of both homologous (homocellular) or differing (heterocellular) cell types, while hemichannels allow for signaling across intracellular and extracellular spaces (Fig. 1).Pannexins were discovered in 2000 [10], and since their discovery, three pannexin proteins: PANX1, PANX2, and PANX3 have been identified and are known to be expressed in the blood vasculature [1]. Pannexins were originally believed to form gap junctions like connexins, due to their predicted protein sequence homology with invertebrate gap junction proteins [10]. One key feature distinguishing pannexins from connexins, however, is that pannexin channels do not typically form gap junctions [11]. Pannexins similarly oligomerize (6 or 8 monomers) to form transmembrane channels [12]; however, extracellular N-glycosylation of pannexin prevents linkage between pannexin channels of neighboring cells (Fig. 1) [13, 14]. Indeed, prevention of this N-glycosylation in vitro does allow pannexin gap junctions to form [14, 15]. Although pannexins form nonselective pores, they are widely recognized for their role in releasing ATP into the extracellular compartment, which can then stimulate adjacent purinergic receptors in both a paracrine and autocrine fashion (Fig. 1) [1, 16].Both connexins and pannexins form nonselective channels with large pores, meaning that any molecule ∼1 kDa or smaller could theoretically traverse the pore lumen (Fig. 1). Since >35,000 metabolites fall within this exclusion limit [9], connexins and pannexins may signal via a wide range of messengers and, thus, can be involved in a large variety of cellular functions. As connexin and pannexin channels can localize to intracellular membranes, the plasma membrane, and to specific microdomains, they play a key role in the influx and efflux of signaling molecules (Fig. 1). While one might suspect this means connexins and pannexins serve redundant functions, in reality each type of connexin and pannexin has varying pore permeabilities, posttranslational modifications, channel gating dynamics, intracellular localization, and cell-type expression profiles. Thus, despite their general similarities, connexins and pannexins provide specialized signaling to the tissues in which they are expressed.Cx37 is primarily expressed in the endothelium, comprising gap junctions between endothelial cells (ECs) and within gap junctions at the myoendothelial junction, a specialized microdomain where ECs send out projections and interact directly with adjacent vascular smooth muscle cells (SMCs) [2]. Cx37 is highly sensitive to flow-dependent signals, and the review by Fang and Burt discusses the role of Cx37 and its various phosphorylation states in cell cycle control, nitric oxide (NO)-dependent modulation of vascular tone, and further details how Cx37 can be upregulated in SMCs to reduce medial thickening following injury [2].Cx40 expression varies throughout the vasculature and has been found in both ECs and SMCs, but it is thought to be predominately expressed in ECs, and much like Cx37, Cx40 is expressed between ECs and in myoendothelial junctions [4]. In the review by Márquez et al. [4], the role of Cx40, in combination with other connexin proteins, in the development of the cardiovascular system is discussed. Further, they explore the essential role for Cx40 in conducted vasodilation, a mechanism whereby electrotonic signals propagate between cells of the vascular wall, primarily through gap junctions, to ensure coordinated changes in diameter within a vascular network [17]. They highlight that Cx40 plays a dual role in blood pressure regulation through its direct actions in the endothelium and by inhibiting renin release from juxtaglomerular cells.Cx43 differs slightly from Cx37 and Cx40 in that it is expressed in pericytes, SMCs, ECs, and the junctions between these cell types, with the cellular expression pattern differing along the arterial tree – from conduit arteries down to capillaries [3]. Sedovy et al. [3] explores the nuances of Cx43 function across vessel types and vascular beds, further describing how Cx43 can modulate restenosis/neointimal formation, vasoreactivity, permeability, and angiogenesis. They also highlight the role of Cx43 in disease...

This study demonstrates real-time measurement of changes in perfusion to pharmacological treatment using laser speckle contrast analysis. Furthermore, this investigation revealed that fasting mice overnight on corncob bedding has differential effects on vascular function and that there was increased fasting blood glucose in mice fasted on corncob bedding compared with paper pulp cellulose bedding. This highlights the impact that bedding type can have on outcomes in vascular and metabolic research and reinforces the need for thorough and robust reporting of animal husbandry practices.