Editorial: Insights in Vascular Physiology 2024

Luis A Martinez-Lemus¹Christopher Garland²Irena Levitan^3*

• ¹University of Missouri, Colombia, United States
• ²Oxford, Oxford, United Kingdom
• ³Department of Medicine, Pulmanary Section, University of Illinois Chicago, Chicago, Illinois, United States

Blood flow is known to be regulated by mechanical forces of shear stress via endothelial mechanotransduction. However, the role of sti ness of vascular smooth muscle cells (VSMCs) in regulation of blood flow is virtually unknown. In this issue, McCallinhart et al present a groundbreaking study Coronary Cytoskeletal Modulation of Coronary Blood Flow in the Presence and Absence of Type 2 Diabetes: The Role of Cofilin demonstrating that cytoskeleton remodeling of VSMCs in type 2 diabetes results in softening of coronary resistance arteries, which augments coronary blood flow. Mechanistically, the authors show that the softening of the VSMCs is mediated by actin-binding protein cofilin, which promotes the disassembly of filamentous actin (F-actin), resulting in a loss of F-actin architecture. This mechanism is proposed to be compensatory to a decrease of coronary blood flow, a known complication of diabetes. Notably, this is in contrast to large arteries that sti en under diabetic conditions, an e ect that has a deleterious e ect on cardiovascular function. This is the first indication that direct modulation of VSMCs cytoskeleton structure can regulate blood flow in vivo. The role of hemodynamic forces in vascular physiology is also addressed in this issue by Kuang et al in their study Fundamental Equations and Hypotheses Governing Glomerular Hemodynamics presenting a new mathematical model of the glomerular hemodynamics in the Hypothesis and Theory category, which helps to understand physics governing glomerular filtration in a more holistic approach. Finally, a review article by Chen et al discusses recent advances in understanding mechanisms of the disruption of the endothelial barrier by low and oscillatory flow. The authors cover complex interactions between endothelial glycocalyx, cytoskeletal and junctional architecture leading to a better understanding of the barrier disruption by proinflammatory flow.Potassium channels play a fundamental role regulating the arterial VSMCs and endothelial cell signaling via nitric oxide (NO) and EDH. Recent research has identified a key role for one form of the delayed rectifier K + channel, KV1.3, in the development of intimal hyperplasia during type 2 diabetes, including in human arteries. As low-grade inflammation is ubiquitous in T2D, the paper by Peraza et al titled A sexdependent role of Kv1.3 channels from macrophages in metabolic syndrome investigated whether other metabolic syndrome related e ects are ameliorated by blocking KV1.3 and demonstrated that blocking these channels had a primary e ect against the infiltration of macrophages in female mice. Another form of K + -channel, the BKCa channel found in VSMCs, not endothelial cells, is linked to spontaneous calcium sparks, with activity suppressing vascular reactivity. These channels can also be influenced by NO. The study by Shvetsova et al titled Dual Role of Calcium-Activated Potassium Channels of High Conductance: Facilitator or Limiter of NO-induced Arterial Relaxation? indicates this is a dual e ect in VSMCs, with BKCa limiting vasodilation to the NO-donor SNP in arteries stimulated with low concentrations of the vasoconstrictor methoxamine. In contrast, with higher concentrations of methoxamine BKCa activity enhanced vasodilation to NO. The authors suggest NO acts indirectly and by inhibiting Ca 2+ entry via VGCC limits BKCa activity during low level vasoconstriction, but as vasoconstriction becomes more intense the influence of BKCa increases, enhancing vasodilation to NO.BKCa channels are sensitive to voltage as well as calcium so it remains to be shown if VSM depolarization is contributing to enhance hyperpolarizing current and thus vasodilation.A significant risk factor for the development of cardiovascular disease is hypertension, which in pregnancy endangers the development of the embryo-fetus as well as the health of the mother. Two prominent characteristics of hypertension are the presence of endothelial dysfunction and arterial sti ening. How these two characteristics of hypertension correlate in pregnant women with chronic hypertension or preeclampsia is revealed in the study of Kaihara et al Di erences between macrovascular and microvascular functions in pregnant women with chronic hypertension and preeclampsia: new insights into maternal vascular health. Their results indicate that increased carotid-femoral pulse wave velocity is consistently present in both chronic hypertension and preeclampsia. At the same time, reactive hyperemia was positively correlated with blood pressure and plasma nitrite (a surrogate of nitric oxide) only in preeclampsia. Because carotid-femoral pulse wave velocity represents large artery sti ness and reactive hyperemia, microvascular function, Kaihara et al. discuss the potential explanation that microvascular endothelial function is preserved in preeclampsia due to its early onset compared to chronic hypertension. An additional explanation is that endothelial dysfunction is not an initial driver of hypertension in preeclampsia. Further interrogation of the potential explanations that Kaihara et al. provide for their results could influence the therapeutic approaches for the treatment of preeclampsia. This issue also includes review articles on targeting NO production and on using the zebrafish as a model of aging. Gonzalez et al Promotion of Nitric Oxide Production: Mechanisms, Strategies, and Possibilities provide a brief but highly comprehensive overview of the targetable mechanisms for promoting NO production. They discuss the strategies currently used in clinical practice and those that remain as potential approaches due to specific limitations, which include specificity issues and the lack of large-scale clinical data, which are appropriately described in the review. Malkinson and Henriques Cerebrovascular ageing: how zebrafish can contribute to solving the puzzle address the potentially impactful role of using zebrafish as a model for studying cerebrovascular aging. They highlight the advantage of assessing longitudinal cerebrovascular changes over the model's lifespan and the capacity to image genetically modified and labeled targets in the whole zebrafish. Another important review article by Lateef et al LIM kinases in cardiovascular health and disease provides a comprehensive review of the roles of LIM kinases, regulators of cytoskeleton dynamics, in cardiovascular cells. LIM kinases are known to be canonical substrates of small Rho-GTPases but in spite of accumulating evidence for their critical roles in cardiovascular system, a comprehensive review has been lacking. Lateef et al provide an in depth analysis of the topic.