Cardiovascular bioimaging of nitric oxide: Achievements, challenges, and the future

Abstract

Nitric oxide (NO) is a ubiquitous, volatile, cellular signaling molecule that operates across a wide physiological concentration range (pM–µM) in different tissues. It is a highly diffusible messenger and intermediate in various metabolic pathways. NO plays a pivotal role in maintaining optimum cardiovascular function, particularly by regulating vascular tone and blood flow. This review highlights the need for accurate, real‐time bioimaging of NO in clinical diagnostic, therapeutic, monitoring, and theranostic applications within the cardiovascular system. We summarize electrochemical, optical, and nanoscale sensors that allow measurement and imaging of NO, both directly and indirectly via surrogate measurements. The physical properties of NO render it difficult to accurately measure in tissues using direct methods. There are also significant limitations associated with the NO metabolites used as surrogates to indirectly estimate NO levels. All these factors added to significant variability in the measurement of NO using available methodology have led to a lack of sensors and imaging techniques of clinical applicability in relevant vascular pathologies such as atherosclerosis and ischemic heart disease. Challenges in applying current methods to biomedical and clinical translational research, including the wide physiological range of NO and limitations due to the characteristics and toxicity of the sensors are discussed, as are potential targets and modifications for future studies. The development of biocompatible nanoscale sensors for use in combination with existing clinical imaging modalities provides a feasible opportunity for bioimaging NO within the cardiovascular system.

Delivery of Nitric Oxide in the Cardiovascular System: Implications for Clinical Diagnosis and Therapy

“…However, due to the difficulties in accurately measuring and controllin NO delivery process within the arteries, only a few products for the market of NO d ery-either diagnostic or therapeutic-have been approved by US Food and Drug ministration (FDA) so far [17,27]. In this tutorial review, we summarized the combin of flow-mediated dilation (FMD) [28,29], computational modeling [30][31][32][33], and nove bioimaging techniques that can assess NO delivery, thereby evaluating endothelial function and its derived CVD [34]. NO-related therapeutic methods, including the release platform, inhaled NO therapy, and potential stem cell therapy were also revie In addition to endogenous delivery, recent advances in exogenous NO release and scavenging technologies have initially realized the modulation of the NO delivery process [17][18][19][20][21][22][23].…”

In Situ Synthesis of Phenoxazine Dyes in Water: A Cutting-Edge Strategy to "Turn-On" Fluorogenic and Chromogenic Detection of Nitric Oxide

“…In addition to its marked reactivity towards nitrosating agents (vide supra), the lack of both visible color absorbance and fluorescence properties for diaryl ether analog 4 then led us to evaluate this structurally simple molecule as a zero-background fluorescent probe for gasotransmitter NO. This ubiquitous cellular signaling molecule is involved in various metabolic pathways and its abnormal levels are often associated with pathological states of various diseases (e.g., cardiovascular diseases [35] , asthma, cancer, neurodegenerative disorders, ...). Consequently, due to this pivotal role, several direct or indirect methods for detecting and quantifying NO levels in different biological matrices have been developed.…”

“…Among these, those based on electrochemical, optical and/or nanoscale sensors/probes are often regarded as promising approaches for accurate and real-time bioimaging of NO, with the aim of facilitating robust biomedical or clinical translational applications (i.e., clinical diagnostics). [35] In the field of small-molecule fluorescent probes responsive to this gasotransmitter [36] , a major breakthrough was achieved by Anslyn and Yang through the design of highly selective low-background imaging agents based on the "covalent-assembly" principle (see introduction section and Figure 2). Indeed, they discovered that non-emissive 2-aminobiphenyl scaffolds were able to selectively create green-yellow-emitting fluorophores based on benzo [c]cinnoline heterocycle, upon their reaction with N2O3 (oxidized surrogate of NO) and under physiological conditions.…”

The Delivery of Nitric Oxide in the Cardiovascular System: Implication for Clinical Diagnosis and Therapy

“…However, due to the difficulties in the accurate measurement and regulation of arterial NO delivery process, few US Food and Drug Administration (FDA)approved diagnostic and therapeutic methods have been proposed for CVD up to now [28]. In this tutorial review, we summarized the combination of flow-mediated dilation (FMD) [29,30], mathematical simulations [31][32][33][34], and novel NO bioimaging techniques that can assess the NO delivery, thereby evaluating the endothelial dysfunction and its derived CVD [35]. The NO-related therapeutic methods, including the inhaled therapy, stem cell therapy and NO-releasing platform were also reviewed.…”