Biology subjects

Cavinato, C.

Publications and source records attributed to Cavinato, C..

8 recordsLinked to original sources

bioRxiv2026

Controlled intramural fluid injection to quantify propensity to thoracic aortic dissection

Dissection of the thoracic aorta includes delamination of medial lamellae and permeation of blood within the media. Quantifying how biaxial loading of a vulnerable wall and fluid mechanics interact to drive dissection remains a central challenge. Here we combine controlled distension-extension testing of intact porcine descending thoracic aortas with forced intramural fluid injection to investigate how axial stretch, injection rate, and needle gauge modulate the initiation and propagation of intramural delamination. Across experiments, injection pressure-volume curves exhibited nonlinear responses characterized by pressure peaks followed by stepwise pressure drops, suggesting progressive micro-delamination events within the medial lamellar networks. Increasing axial stretch significantly elevated peak injection pressure and promoted preferential axial propagation of the permeation / delamination front. Higher injection rates induced abrupt lamellar separation and larger dissected areas, whereas smaller needle gauges generated higher upstream pressures due to increased hydraulic resistance. Synchrotron imaging revealed the microstructural transition from intralamellar fluid permeation and wall swelling to the formation of a large fluid-filled delamination cavity. These results support a mechanistic framework in which the introduction of pressurized fluid within the aortic media behaves as a hydraulic fracture process in a layered poroelastic tissue, governed by balance across fluid pressurization, wall loading, and interlamellar strength. The findings provide quantitative insight into the biomechanical conditions that contribute to the initiation and propagation of aortic dissection.

bioengineering↗

bioRxiv2025

Growth Arrest of Thoracic Aortic Aneurysms in Aging Marfan Mice

There is a pressing need to identify pathologic mechanisms that render a thoracic aortic aneurysm susceptible to continued enlargement, dissection, or rupture, but additional insight can be gleaned by understanding potential compensatory mechanisms that prevent disease progression and thereby stabilize a lesion. Our biomechanical data suggest that the ascending aorta within a common mouse model of Marfan syndrome, Fbn1C1041G/+, exhibits progressive disease from 12 weeks to 1 year of age, but near growth arrest from 1 to 2 years of age. Comparison of the biomechanical phenotype, histological characteristics, proteomic signature, and transcriptional profile from 12 weeks to 1 year to 2 years suggests that numerous differentially expressed genes (including downregulated Ilk, Ltbp3, and Rictor) and associated proteins may contribute to late-term growth arrest. There is also a conspicuous absence of proteins associated with inflammation from 1 to 2 years of age. Although there is a need to understand better the interconnected roles of temporal changes in differential gene expression and protein abundance, reducing mTOR signaling and reducing excessive inflammation appears to merit increased attention in preventing continued aneurysmal expansion in Marfan syndrome.

bioengineering↗

bioRxiv2025

Proximal Pulmonary Artery Stiffening as a Biomarker of Cardiopulmonary Aging

The geroscience hypothesis suggests that understanding underlying ageing mechanisms will enable us to delay aging and lessen age-related disability and diseases. While hallmarks of ageing list multiple contributing factors, role of mechanics has only been recently recognized and increasingly appreciated. Here, we use mouse models of ageing to investigate changes in mechanics of the proximal pulmonary artery, lung and right ventricle function in ageing. We found an age-related decline in the capacity to store energy and increased circumferential stiffness of the proximal pulmonary artery with age that associated with a reorientation of collagen towards the circumferential direction, decreased exercise ability, and decreased function of the lung and right ventricle. The observed compromised mechanics in proximal pulmonary artery is consistent across multiple mouse models of accelerated ageing. Further, transcriptional changes in proximal pulmonary artery indicate that aging is associated with senescence of perivascular macrophages, adventitial fibroblasts, and medial smooth muscle cells. Older pulmonary arteries increase expression of genes associated with ECM turnover (including genes in the TGF{beta} pathway) and increased intercellular signaling amongst perivascular macrophages, fibroblasts and smooth muscle cells. Our results provide promising biomarkers of ageing for diagnosis and potential pathways and molecular targets for targeting anti-ageing therapies.

physiology↗

bioRxiv2025

Hypoxia-Induced Cardiopulmonary Remodeling and Recovery: Critical Roles of the Proximal Pulmonary Artery, Macrophages, and Exercise

Hypoxemia impairs cardiopulmonary function. We investigated pulmonary artery remodeling in mice exposed to chronic hypoxia for up to five weeks and quantified associated changes in cardiac and lung function, without or with subsequent normoxic recovery in the absence or presence of exercise or pharmacological intervention. Hypoxia-induced stiffening of the proximal pulmonary artery stemmed primarily from remodeling of the adventitial collagen, which resulted in part from altered inter-cellular signaling associated with phenotypic changes in the mural smooth muscle cells and macrophages. Such stiffening appeared to precede and associate with both right ventricular and lung dysfunction, with changes emerging to similar degrees regardless of the age of onset of hypoxia during postnatal development. Key homeostatic target values of the wall mechanics were recovered by the pulmonary arteries with normoxic recovery while other values recovered only partially. Overall cardiopulmonary dysfunction due to hypoxia was similarly only partially reversible. Remodeling of the cardiopulmonary system due to hypoxia is a complex, multi-scale process that involves maladaptations of the proximal pulmonary artery.

physiology↗

bioRxiv2023

Smooth Muscle Cell Death Drives an Osteochondrogenic Phenotype and Severe Proximal Vascular Disease in Progeria

Hutchinson-Gilford Progeria Syndrome results in rapid aging and severe cardiovascular sequelae that accelerate near end of life. We associate progressive deterioration of arterial structure and function with single cell transcriptional changes, which reveals a rapid disease process in proximal elastic arteries that largely spares distal muscular arteries. These data suggest a novel sequence of progressive vascular disease in progeria: initial extracellular matrix remodeling followed by mechanical stress-induced smooth muscle cell death in proximal arteries, leading a subset of remnant smooth muscle cells to an osteochondrogenic phenotypic modulation that results in an accumulation of proteoglycans that thickens the wall and increases pulse wave velocity, with late calcification exacerbating these effects. Increased pulse wave velocity drives left ventricular diastolic dysfunction, the primary diagnosis in progeria children. Mitigating smooth muscle cell loss / phenotypic modulation promises to have important cardiovascular implications in progeria patients.

bioengineering↗

bioRxiv2022

Fibronectin-integrin α5 signaling promotes thoracic aortic aneurysm in a mouse model of Marfan syndrome

BackgroundMarfan syndrome, caused by mutations in the gene for the extracellular matrix (ECM) glycoprotein fibrillin-1, leads to thoracic aortic aneurysms (TAAs). Phenotypic modulation of vascular smooth muscle cells (SMCs) and ECM remodeling are characteristics of both non-syndromic and Marfan aneurysms. The ECM protein fibronectin (FN) is elevated in the tunica media of TAAs and amplifies inflammatory signaling in endothelial and SMCs through its main receptor, integrin 5{beta}1. We investigated the role of integrin 5-specific signals in Marfan mice in which the cytoplasmic domain of integrin 5 was replaced with that of integrin 2 (denoted 5/2 chimera). MethodsWe used 5/2 chimera mouse crossed with Fbn1mgR/mgR genetic background (mgR, a mouse model of Marfan syndrome) to compare the survival rate and pathogenesis of TAAs among wild type, 5/2, mgR and 5/2; mgR mice. Further biochemical and microscopic analysis of porcine and mouse aortic SMCs allowed us to identify the molecular mechanisms by which FN affects SMCs and subsequent development of TAAs. ResultsFN was elevated in the thoracic aortas from Marfan patients, in non-syndromic aneurysms and in the mgR mouse model of Marfan syndrome. The 5/2 mutation greatly prolonged survival of Marfan mice, with improved elastic fiber integrity, mechanical properties, SMC density, and SMC contractile gene expression. Furthermore, in vitro, plating of wild-type, but not 5/2, SMCs on FN decreased contractile gene expression and activated inflammatory pathways. These effects correlated with increased NF-kB activation and immune cell infiltration in the mgR aortas, which was rescued in the 5/2 mgR aortas. ConclusionsFN-integrin 5 signaling is a significant driver of TAA in the mgR mouse model. This pathway warrants further investigation as a therapeutic target.

pathology↗

bioRxiv2022

Compensatory aortic remodeling in Marfan syndrome protects against sexually dimorphic rupture during a BAPN challenge

Transmural rupture of the aorta is responsible for significant morbidity and mortality; it occurs when wall stress exceeds local wall strength. Amongst other conditions, the aortic root and ascending aorta become vulnerable to dissection and rupture in Marfan syndrome, a connective tissue disorder that results in a progressive fragmentation and degradation of the elastic fibers of the aortic wall. Whereas competent elastic fibers are critical for aortic functionality, cross-linked collagen fibers endow the aorta with its stiffness and strength. In this paper, we contrast progressive degeneration of the ascending aorta in male and female Marfan and wild-type mice, with and without chronic exposure to a potent inhibitor of lysyl oxidase ({beta}-aminopropionitrile, or BAPN), to examine effects of extracellular matrix cross-linking in aortic dilatation and rupture. We found a strong sexual dimorphism in aortic dilatation in Marfan mice and aortic rupture in wild-type mice, but also a compensatory remodeling of the aorta that protected the Marfan aorta against lethal rupture despite a strong BAPN challenge. This compensation appears to be mediated via increased lysyl oxidase in the female and especially male Marfan aorta, resulting in improved collagen fiber stability and integrity, particularly of fibril bundles in the adventitia.

bioengineering↗

bioRxiv2021

Critical Pressure of Intramural Delamination in Aortic Dissection

Computational models of aortic dissection can examine mechanisms by which this potentially lethal condition develops and propagates. We present results from phase-field finite element simulations that are motivated by a classical but seldom repeated experiment. Initial simulations agreed qualitatively and quantitatively with data, yet because of the complexity of the problem it was difficult to discern trends. Simplified analytical models were used to gain further insight. Together, simplified and phase-field models reveal power-law-based relationships between the pressure that initiates an intramural tear and key geometric and mechanical factors - insult surface area, wall stiffness, and tearing energy. The degree of axial stretch and luminal pressure similarly influence the pressure of tearing, which was [~]88 kPa for healthy and diseased human aortas having sub-millimeter-sized initial insults, but lower for larger tear sizes. Finally, simulations show that the direction a tear propagates is influenced by focal regions of weakening or strengthening, which can drive the tear towards the lumen (dissection) or adventitia (rupture). Additional data on human aortas having different predisposing disease conditions will be needed to extend these results further, but the present findings show that physiologic pressures can propagate initial medial defects into delaminations that can serve as precursors to dissection.

bioengineering↗