Understanding Vascular Reactivity

Abstract

Blood vessels form an intricate network of dynamic conduits responsible for delivering blood throughout the body. Consequently, the structural and functional integrity of blood vessels is critical for optimal circulation and tissue function. Vascular reactivity is an essential physiological process by which blood vessels dynamically adjust their diameter in response to various stimuli. This adaptive process ensures that blood flow meets tissue-specific metabolic demands. Vascular reactivity is also essential for controlling blood pressure, as changes in the radius of resistance vessels dramatically affect peripheral vascular resistance.

Vascular reactivity is governed by sophisticated signaling cascades within and between various cell types constituting the vascular wall (smooth muscle cells, pericytes, and endothelial cells), perivascular adipose tissue that surrounds most blood vessels, and many types of additional extravascular cells. These diverse signaling cascades give rise to regional heterogeneity in vascular responses, leading to distinctive reactivity patterns tailored to the physiological role of individual vessel segments. An array of different hormones and circulating factors can also influence vascular reactivity, and considering sex as a biological variable has provided valuable insights into the mechanisms underlying vascular function.

The importance of vascular reactivity extends beyond basic vessel physiology, as its altered function underpins physiological vascular adaptation during pregnancy and numerous pathological conditions such as hypertension, heart failure, and stroke. Thus, elucidating the intricate mechanisms, functional implications, and adaptive responses, as well as developing new tools and approaches to better study vascular reactivity, is paramount for advancing cardiovascular research and the development of new treatment strategies.

In this Special Topics Issue (STI), we present a curated collection of reviews and original studies that expand our current knowledge of mechanisms and functional implications of vascular reactivity in health, physiological adaptation, and disease states. The reader will also find studies introducing innovative methodological approaches and analytical techniques for examining vascular reactivity, creating opportunities to advance future research endeavors in vascular biology.

This STI begins with a review by Li and colleagues [1] dissecting the role of ion channels in vascular cells and their contributions to vascular hyporesponsiveness during shock. The authors examine how structural and functional alterations in various ion channels (e.g., K⁺, Ca²⁺, and Na⁺ channels) contribute to altered vascular reactivity during shock and how this new mechanistic insight could be exploited for the development of new therapies to treat shock-induced vascular complications.

Following the ion channel theme, Mbiakop and Jaggar [2] examined the emerging role of polycystin proteins (PKD1 and PKD2) in vascular function during physiological and pathological conditions such as hypertension. Specifically, the authors focused on PKD1 and PKD2 expression and activation in arterial smooth muscle and endothelial cells where these proteins can mediate the regulation of vascular tone and blood pressure. Examining PKD1 and PKD2 distribution, regulation, and function is fertile ground for additional research and to bridge findings suggesting additional roles for these ion channels.

The work of Wang and colleagues [3] summarized the role of vacuolar H⁺-ATPase, a multisubunit protein complex that regulates pH in cellular compartments and the extracellular space, in the pathophysiology of diabetes, hypertension, and atherosclerosis. The authors highlight current knowledge of how V-ATPase contributes to these conditions through various mechanisms, including alterations in insulin signaling, sodium homeostasis, and cholesterol metabolism. This new knowledge could be used to identify new therapeutic targets.

The next review by Ritsvall and Albinsson [4] explored the emerging role of YAP/TAZ (Yes-associated protein and WW domain-containing transcription regulator 1) as critical mechanosensitive transcriptional coactivators in vascular mechanotransduction and disease. This topic is significant given recent insight indicating that YAP/TAZ activity plays a key role in maintaining vascular integrity and the links of the signaling pathway with aging and vascular disease development.

The final review by Osikoya and colleagues [5] dives into the role of perivascular adipose tissue (PVAT) in pregnancy-induced uterine artery adaptations. This manuscript highlights how PVAT influences vascular reactivity and blood flow in the uterine circulation during pregnancy. This topic is highly significant given that proper uterine artery adaptations are essential for healthy pregnancy outcomes by facilitating sufficient blood supply to the developing fetus and placenta. Conversely, aberrant vascular adaptations are associated with pregnancy complications, including intrauterine growth restriction and preeclampsia.

In the first original manuscript, Singhrao and colleagues [6] investigated how nicotine impairs β-adrenergic-mediated cyclic adenosine monophosphate (cAMP) signaling in vascular smooth muscle. They correlated impaired cAMP signaling in vascular smooth muscle with reduced vasodilation. The findings are significant because they reveal a mechanism by which nicotine, which could be obtained from cigarettes and other nicotine-delivery products, may contribute to vascular dysfunction and cardiovascular complications.

Howe and Bent [7] explored how different regions of the human foot sole respond to pressure through microvascular reactivity—blood flow changes after pressure release. The authors found that areas typically under higher pressure during standing, like the metatarsals, show stronger protective responses than low-pressure areas, such as the medial arch. This observation led the authors to argue that regional differences in microvascular reactivity across the foot sole provide critical insights into protective mechanisms against pressure-induced ischemia and a framework for ulcer risk assessment.

A report from Traylor and colleagues [8] examined sex-specific differences in microvascular reactivity and hemodynamic responses to passive limb heating in young adults. The study found that while men and women had similar blood flow when normalized to forearm lean mass, men still exhibited greater reoxygenation rates following ischemia. The findings highlight that blood flow alone is not the primary factor causing sex differences in microvascular reactivity. Results add to our understanding of sex-specific cardiovascular function.

The study presented by Heitmar and colleagues [9] reported the case of a patient with arrhythmia who showed distinct patterns of retinal vessel oscillations compared to a healthy control. The authors suggest that retinal vascular dynamics could provide a window for observing irregular heartbeats. Moreover, they propose that noninvasive assessment of retinal vessels offers valuable diagnostic information about microvascular function and serves as an alternative to ECG for assessing cardiac arrhythmias.

The remaining two studies described new techniques to study vascular function, including reactivity. In the first paper by Burboa et al. [10], the authors examined how different matrix gel substrates (gelatin vs. fibronectin) affect the function of primary cultured microvascular endothelial cells from mouse mesenteric arteries. The authors found that gelatin-cultured cells exhibit electrical behaviors that are more similar to those of the intact endothelium. The research establishes reliable methods for culturing microvascular endothelial cells with properties closely resembling the in vivo state, which is critical to examining vascular function in health and disease.

Finally, the study by Evans and colleagues [11] presented a novel methodological approach that combines in vivo two-photon and laser speckle microscopy with ex vivo capillary-parenchymal arteriole (CaPA) preparation to study neurovascular coupling in the brain. Accordingly, when significant alterations in blood vessel reactivity are detected during live imaging, the CaPA preparation will facilitate a detailed investigation of the underlying mechanisms behind these observed changes in arteries from the same mouse. By combining complementary in vivo and ex vivo approaches to study vascular reactivity, deeper insight into both normal and abnormal cerebrovascular function could be gained, thus further enhancing our understanding of neurovascular coupling.

In summary, this collection of articles pushes the boundaries by defining critical knowledge gaps, providing new insight, and suggesting innovative concepts and ideas that should drive the vascular reactivity field for years to come.

Vascular reactivity is a dynamic process by which blood vessels adjust their diameter to meet physiological demands. This Special Topic Issue highlights the multifaceted nature of vascular reactivity through a collection of reviews and original studies that aim to provide insight into this relevant process. Key themes include the critical roles of ion channels in maintaining vascular tone, the importance of mechanotransduction through YAP/TAZ signaling, and the influence of perivascular adipose tissue on pregnancy-related vascular adaptations. The original research contributions offer valuable insights into how nicotine impairs vasodilation through disrupted cAMP signaling, regional differences in microvascular reactivity within the foot, and sex-specific variations in vascular responses. Methodological innovations, such as retinal vessel assessment for detecting arrhythmias and combined in vivo and ex vivo approaches for studying neurovascular coupling, further advance the field. By illuminating the complex mechanisms and adaptations of vascular reactivity across various physiological and pathological states, this Special Topic Issue provides critical knowledge gaps and proposes innovative concepts to guide future research on vascular reactivity and therapeutic development.

The authors have nothing to report.