Dysregulations of Key Regulators of Angiogenesis and Inflammation in Abdominal Aortic Aneurysm

Zalewski, Daniel; Chmiel, Paulina; Kołodziej, Przemysław; Borowski, Grzegorz; Feldo, Marcin; Kocki, Janusz; Bogucka‐Kocka, Anna

doi:10.3390/ijms241512087

Cited by 9 publications

(3 citation statements)

References 73 publications

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“…MMP2 activates TGFβ1 signaling and plays an important role in arterial aging, a risk factor for developing AAA. TGFβ1 expression has been significantly increased in the plasma of AAA patients 30 or patients with aortic dilatation 31 . However, the role of TGFβ1 in AAA development in mice is controversial, with studies reporting both beneficial 32 and detrimental 33 effects.…”

Section: Resultsmentioning

confidence: 99%

Thymidine Phosphorylase Promotes the Formation of Abdominal Aortic Aneurysm in Mice Fed a Western Diet

Hong,

Yue,

Cai

et al. 2024

Preprint

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AimsThe precise molecular drivers of abdominal aortic aneurysm (AAA) remain unclear. Thymidine phosphorylase (TYMP) contributes to increased platelet activation, thrombosis, and inflammation, all of which are key factors in AAA development. Additionally, TYMP suppresses the proliferation of vascular smooth muscle cells (VSMCs), which are central to the development and progression of AAA. We hypothesize that TYMP plays a key role in AAA development.Methods and ResultsWe conducted a histological study using human AAA samples and normal abdominal aortas, revealing heightened levels of TYMP in human AAA vessel walls. To validate this observation, we utilized an Ang II perfusion-induced AAA model in wild-type C57BL/6J (WT) andTymp−/−mice, feeding them a Western diet (TD.88137) starting from 4 weeks of age. We found thatTymp−/−mice were protected from Ang II perfusion-induced AAA formation. Furthermore, by using TYMP-expressing VSMCs as well as primarily cultured VSMCs from WT andTymp−/−mice, we elucidated the essential role of TYMP in regulating MMP2 expression and activation. TYMP deficiency or inhibition by tipiracil, a selective TYMP inhibitor, led to reduced MMP2 production, release, and activation in VSMCs. Additionally, TYMP was found to promote pro-inflammatory cytokine expression systemically, and its absence attenuates TNF-α-stimulated activation of MMP2 and AKT. By co-culturing VSMCs and platelets, we observed that TYMP-deficient platelets had a reduced inhibitory effect on VSMC proliferation compared to WT platelets. Moreover, TYMP appeared to enhance the expression of activated TGFβ1 in cultured VSMCs in vitro and in human AAA vessel walls in vivo. TYMP also boosted the activation of thrombospondin-1 type 1 repeat domain-enhanced TGFβ1 signaling, resulting in increased connective tissue growth factor production.ConclusionOur findings collectively demonstrated that TYMP serves as a novel regulatory force in vascular biology, exerting influence over VSMC functionality and inflammatory responses that promote the development of AAA.Translational PerspectiveThymidine phosphorylase (TYMP) is increased in the vessel walls of patients with abdominal aortic aneurysm (AAA), and TYMP deficiency in mice reduces the incidence of AAA, suggesting that TYMP plays a crucial role in AAA development. This could be attributed to TYMP’s role in enhancing systemic inflammation and thrombosis, inhibiting vascular smooth muscle cell function, increasing the activation of matrix metalloproteinase and AKT, as well as enhancing the expression of TGFβ1 and connective tissue growth factor. Tipiracil is an FDA-approved drug known to inhibit TYMP-enhanced thrombosis. Targeting TYMP with tipiracil could represent a promising new therapeutic strategy for AAA development.

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Section: Resultsmentioning

confidence: 99%

Thymidine Phosphorylase Promotes the Formation of Abdominal Aortic Aneurysm in Mice Fed a Western Diet

Hong,

Yue,

Cai

et al. 2024

Preprint

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“…Each pathway accelerates the progression of AAA by widening the artery wall as a result of changing VSMCs' phenotype, apoptosis and ECM weakening. TGF-α and TGF-β1 modulate both the PI3K/Akt and NFκB signaling pathways, which contribute to aneurysm development [100].…”

Section: Chymase and Tryptasementioning

confidence: 99%

Cellular, Molecular and Clinical Aspects of Aortic Aneurysm—Vascular Physiology and Pathophysiology

Domagała,

Data,

Szyller

et al. 2024

Cells

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A disturbance of the structure of the aortic wall results in the formation of aortic aneurysm, which is characterized by a significant bulge on the vessel surface that may have consequences, such as distention and finally rupture. Abdominal aortic aneurysm (AAA) is a major pathological condition because it affects approximately 8% of elderly men and 1.5% of elderly women. The pathogenesis of AAA involves multiple interlocking mechanisms, including inflammation, immune cell activation, protein degradation and cellular malalignments. The expression of inflammatory factors, such as cytokines and chemokines, induce the infiltration of inflammatory cells into the wall of the aorta, including macrophages, natural killer cells (NK cells) and T and B lymphocytes. Protein degradation occurs with a high expression not only of matrix metalloproteinases (MMPs) but also of neutrophil gelatinase-associated lipocalin (NGAL), interferon gamma (IFN-γ) and chymases. The loss of extracellular matrix (ECM) due to cell apoptosis and phenotype switching reduces tissue density and may contribute to AAA. It is important to consider the key mechanisms of initiating and promoting AAA to achieve better preventative and therapeutic outcomes.

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“…Endostatin inhibits endothelial proliferation, and is one of the most potent inhibitors of angiogenesis and tumor growth [ 157 , 158 ]. It has potential implications in AAA due to its ability to inhibit angiogenesis and stabilize the vasculature, as well as its anti-inflammatory effects [ 159 ]. One study investigated baseline endostatin levels and aortic expansion rate.…”

Section: Prognostic Protein Categorization and Functionsmentioning

confidence: 99%

Current Prognostic Biomarkers for Abdominal Aortic Aneurysm: A Comprehensive Scoping Review of the Literature

Khan,

Abu-Raisi,

Feasson

et al. 2024

Biomolecules

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Abdominal aortic aneurysm (AAA) is a progressive dilatation of the aorta that can lead to aortic rupture. The pathophysiology of the disease is not well characterized but is known to be caused by the general breakdown of the extracellular matrix within the aortic wall. In this comprehensive literature review, all current research on proteins that have been investigated for their potential prognostic capabilities in patients with AAA was included. A total of 45 proteins were found to be potential prognostic biomarkers for AAA, predicting incidence of AAA, AAA rupture, AAA growth, endoleak, and post-surgical mortality. The 45 proteins fell into the following seven general categories based on their primary function: (1) cardiovascular health, (2) hemostasis, (3) transport proteins, (4) inflammation and immunity, (5) kidney function, (6) cellular structure, (7) and hormones and growth factors. This is the most up-to-date literature review on current prognostic markers for AAA and their functions. This review outlines the wide pathophysiological processes that are implicated in AAA disease progression.

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Dysregulations of Key Regulators of Angiogenesis and Inflammation in Abdominal Aortic Aneurysm

Cited by 9 publications

References 73 publications

Thymidine Phosphorylase Promotes the Formation of Abdominal Aortic Aneurysm in Mice Fed a Western Diet

Thymidine Phosphorylase Promotes the Formation of Abdominal Aortic Aneurysm in Mice Fed a Western Diet

Cellular, Molecular and Clinical Aspects of Aortic Aneurysm—Vascular Physiology and Pathophysiology

Current Prognostic Biomarkers for Abdominal Aortic Aneurysm: A Comprehensive Scoping Review of the Literature

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