Gurgone, Danila (2020) Evaluation of vascular reactivity in physiological and pathological conditions. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Resource language: English
Title: Evaluation of vascular reactivity in physiological and pathological conditions
Date: 10 March 2020
Number of Pages: 129
Institution: Università degli Studi di Napoli Federico II
Department: Farmacia
Dottorato: Scienza del farmaco
Ciclo di dottorato: 32
Coordinatore del Corso di dottorato:
Sorrentino, RaffaellaUNSPECIFIED
Maffia, PasqualeUNSPECIFIED
Date: 10 March 2020
Number of Pages: 129
Keywords: Vasodilation; Endothelium dysfunction; Hydrogen sulfide; Nitric Oxide; Cardiovascular diseases; Respiratory allergic diseases; Oxidative stress
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/14 - Farmacologia
Date Deposited: 09 Apr 2020 15:05
Last Modified: 04 Apr 2022 08:45

Collection description

Gasotransmitters are small gaseous and biologically active molecules contributing to the control of vasodilation. Vasodilation is a physiological event necessary for human cardiovascular wellbeing. The major gasotransmitters involved in vascular relaxation are nitric oxide (NO) and hydrogen sulfide (H2S). A wide range of evidence showed that NO and H2S independently affect the vasculature, while other studies tried to address their cooperation in the control of vascular tone. However, the molecular mechanisms regulating NO and H2S mutual interaction still need to be fully elucidated. The cystathionine beta-synthase (CBS) is an H2S-producing enzyme, and its mutation leads to a severe high plasmatic level of homocysteine. This medical condition is strongly associated with endothelium dysfunction. L-serine is synthetized from L-cysteine by CBS activity during the H2S production. On the other hand, L-serine is involved in the synthesis of sphingosine-1-phosphate (S1P), a well-known NO trigger. The first part of this thesis focused on the study of the vascular effect of L-serine compared to L-cysteine and to evaluate if the L-cysteine/H2S signalling is associated to the L-serine/S1P/NO pathway in the vasculature through CBS activity. We demonstrated that L-cysteine and L-serine were able to induce vascular relaxation in an endothelium-dependent manner through the activation of the NO/S1P pathway. Then we demonstrated that L-cysteine was able to produce NO trough the involvement of CBS and to increase the level of S1P in aortic tissue. Finally, we demonstrated that CBS is expressed in the same endothelial cellular cavity of the endothelium NO-producing enzyme (eNOS). In summary, our results indicate that the CBS enzyme plays a role in the control of vascular homeostasis not only as of the main endogenous source of H2S but also by interfering with the S1P/NO signalling through the L-serine. These data suggest a mechanism of action that may in part explain the severe cardiovascular pathology observed in patients affected by CBS deletion. The second part of this thesis focused on the study of the alteration of systemic vascular reactivity as a secondary outcome in airways allergic inflammatory diseases. It is well known that changing in the endothelium physiology leads to the initiation of CVD. However, the published clinical studies on the association among respiratory allergic diseases and CVD are controversial, and the literature is pauper of pre-clinical evidence on the effect of allergy on the systemic vasculature. We showed that a condition of systemic and pulmonary inflammation induced by an allergic stimulus impairs the systemic vasculature, alters the protein expression of the major enzymes involved in vascular functionality (i.e. eNOS, NADPH oxidase 1 and 4) and increases the expression of vascular pro-inflammatory genes. This evidence tried to unravel the correlation between allergic respiratory diseases and cardiovascular diseases.


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