Mechanotransduction and extracellular matrix homeostasis.

Soft connective tissues at steady state are dynamic; resident cells continually read environmental cues and respond to them to promote homeostasis, including maintenance of the mechanical properties of the extracellular matrix (ECM) that are fundamental to cellular and tissue health. The mechanosensing process involves assessment of the mechanics of the ECM by the cells through integrins and the actomyosin cytoskeleton, and is followed by a mechanoregulation process, which includes the deposition, rearrangement or removal of the ECM to maintain overall form and function. Progress towards understanding the molecular, cellular and tissue-level effects that promote mechanical homeostasis has helped to identify key questions for future research.

VEuPathDB: the eukaryotic pathogen, vector and host bioinformatics resource center in 2023.

The Eukaryotic Pathogen, Vector and Host Informatics Resource (VEuPathDB, https://veupathdb.org) is a Bioinformatics Resource Center funded by the National Institutes of Health with additional funding from the Wellcome Trust. VEuPathDB supports >600 organisms that comprise invertebrate vectors, eukaryotic pathogens (protists and fungi) and relevant free-living or non-pathogenic species or hosts. Since 2004, VEuPathDB has analyzed omics data from the public domain using contemporary bioinformatic workflows, including orthology predictions via OrthoMCL, and integrated the analysis results with analysis tools, visualizations, and advanced search capabilities. The unique data mining platform coupled with >3000 pre-analyzed data sets facilitates the exploration of pertinent omics data in support of hypothesis driven research. Comparisons are easily made across data sets, data types and organisms. A Galaxy workspace offers the opportunity for the analysis of private large-scale datasets and for porting to VEuPathDB for comparisons with integrated data. The MapVEu tool provides a platform for exploration of spatially resolved data such as vector surveillance and insecticide resistance monitoring. To address the growing body of omics data and advances in laboratory techniques, VEuPathDB has added several new data types, searches and features, improved the Galaxy workspace environment, redesigned the MapVEu interface and updated the infrastructure to accommodate these changes.

Homeostatic, Non-Canonical Role of Macrophage Elastase in Vascular Integrity.

BACKGROUND: Matrix metalloproteinase (MMP)-12 is highly expressed in abdominal aortic aneurysms and its elastolytic function has been implicated in the pathogenesis. This concept is challenged, however, by conflicting data. Here, we sought to revisit the role of MMP-12 in abdominal aortic aneurysm. METHODS: Apoe-/- and Mmp12-/-/Apoe-/- mice were infused with Ang II (angiotensin). Expression of neutrophil extracellular traps (NETs) markers and complement component 3 (C3) levels were evaluated by immunostaining in aortas of surviving animals. Plasma complement components were analyzed by immunoassay. The effects of a complement inhibitor, IgG-FH1-5 (factor H-immunoglobulin G), and macrophage-specific MMP-12 deficiency on adverse aortic remodeling and death from rupture in Ang II-infused mice were determined. RESULTS: Unexpectedly, death from aortic rupture was significantly higher in Mmp12-/-/Apoe-/- mice. This associated with more neutrophils, citrullinated histone H3 and neutrophil elastase, markers of NETs, and C3 levels in Mmp12-/- aortas. These findings were recapitulated in additional models of abdominal aortic aneurysm. MMP-12 deficiency also led to more pronounced elastic laminae degradation and reduced collagen integrity. Higher plasma C5a in Mmp12-/- mice pointed to complement overactivation. Treatment with IgG-FH1-5 decreased aortic wall NETosis and reduced adverse aortic remodeling and death from rupture in Ang II-infused Mmp12-/- mice. Finally, macrophage-specific MMP-12 deficiency recapitulated the effects of global MMP-12 deficiency on complement deposition and NETosis, as well as adverse aortic remodeling and death from rupture in Ang II-infused mice. CONCLUSIONS: An MMP-12 deficiency/complement activation/NETosis pathway compromises aortic integrity, which predisposes to adverse vascular remodeling and abdominal aortic aneurysm rupture. Considering these new findings, the role of macrophage MMP-12 in vascular homeostasis demands re-evaluation of MMP-12 function in diverse settings.

Hemodynamics and Wall Mechanics of Vascular Graft Failure.

Blood vessels are subjected to complex biomechanical loads, primarily from pressure-driven blood flow. Abnormal loading associated with vascular grafts, arising from altered hemodynamics or wall mechanics, can cause acute and progressive vascular failure and end-organ dysfunction. Perturbations to mechanobiological stimuli experienced by vascular cells contribute to remodeling of the vascular wall via activation of mechanosensitive signaling pathways and subsequent changes in gene expression and associated turnover of cells and extracellular matrix. In this review, we outline experimental and computational tools used to quantify metrics of biomechanical loading in vascular grafts and highlight those that show potential in predicting graft failure for diverse disease contexts. We include metrics derived from both fluid and solid mechanics that drive feedback loops between mechanobiological processes and changes in the biomechanical state that govern the natural history of vascular grafts. As illustrative examples, we consider application-specific coronary artery bypass grafts, peripheral vascular grafts, and tissue-engineered vascular grafts for congenital heart surgery as each of these involves unique circulatory environments, loading magnitudes, and graft materials.

Developmental changes in lung function of mice are independent of sex as a biological variable.

Pulmonary function testing (PFT) in mice includes biomechanical assessment of lung function relevant to physiology in health and its alteration in disease, hence, it is frequently used in preclinical modeling of human lung pathologies. Despite numerous reports of PFT in mice of various ages, there is a lack of reference data for developing mice collected using consistent methods. Therefore, we profiled PFTs in male and female C57BL/6J mice from 2 to 23 wk of age, providing reference values for age- and sex-dependent changes in mouse lung biomechanics during development and young adulthood. Although males and females have similar weights at birth, females weigh significantly less than males after 5 wk of age (P < 0.001) with largest weight gain observed between 3 and 8 wk in females and 3 and 13 wk in males, after which weight continued to increase more slowly up to 23 wk of age. Lung function parameters including static compliance and inspiratory capacity also increased rapidly between 3 and 8 wk in female and male mice, with male mice having significantly greater static compliance and inspiratory capacity than female mice (P < 0.001). Although these parameters appear higher in males at a given age, allometric scaling showed that static compliance and inspiratory compliance were comparable between the two sexes. This suggests that differences in measurements of lung function are likely body weight-based rather than sex-based. We expect these data to facilitate future lung disease research by filling a critical knowledge gap in our field.NEW & NOTEWORTHY This study provides reference values for changes in mouse lung biomechanics from 2 to 23 wk of age. There are rapid developmental changes in lung structure and function of male and female mice between the ages of 3 and 8 wk. Male mice become noticeably heavier than female mice at or about 5 wk of age. We identified that differences in normal lung function measurements are likely weight-based, not sex-based.

Tissue Engineering of Vascular Grafts: A Case Report From Bench to Bedside and Back.

For over 25 years, our group has used regenerative medicine strategies to develop improved biomaterials for use in congenital heart surgery. Among other applications, we developed a tissue-engineered vascular graft (TEVG) by seeding tubular biodegradable polymeric scaffolds with autologous bone marrow-derived mononuclear cells. Results of our first-in-human study demonstrated feasibility as the TEVG transformed into a living vascular graft having an ability to grow, making it the first engineered graft with growth potential. Yet, outcomes of this first Food and Drug Administration-approved clinical trial evaluating safety revealed a prohibitively high incidence of early TEVG stenosis, preventing the widespread use of this promising technology. Mechanistic studies in mouse models provided important insight into the development of stenosis and enabled advanced computational models. Computational simulations suggested both a novel inflammation-driven, mechano-mediated process of in vivo TEVG development and an unexpected natural history, including spontaneous reversal of the stenosis. Based on these in vivo and in silico discoveries, we have been able to rationally design strategies for inhibiting TEVG stenosis that have been validated in preclinical large animal studies and translated to the clinic via a new Food and Drug Administration-approved clinical trial. This progress would not have been possible without the multidisciplinary approach, ranging from small to large animal models and computational simulations. This same process is expected to lead to further advances in scaffold design, and thus next generation TEVGs.

Effects of Age, Sex, and Extracellular Matrix Integrity on Aortic Dilatation and Rupture in a Mouse Model of Marfan Syndrome.

BACKGROUND: Transmural failure of the aorta is responsible for substantial morbidity and mortality; it occurs when mechanical stress exceeds strength. The aortic root and ascending aorta are susceptible to dissection and rupture in Marfan syndrome, a connective tissue disorder characterized by a progressive reduction in elastic fiber integrity. Whereas competent elastic fibers endow the aorta with compliance and resilience, cross-linked collagen fibers confer stiffness and strength. We hypothesized that postnatal reductions in matrix cross-linking increase aortopathy when turnover rates are high. METHODS: We combined ex vivo biaxial mechanical testing with multimodality histological examinations to quantify expected age- and sex-dependent structural vulnerability of the ascending aorta in Fbn1C1041G/+ Marfan versus wild-type mice without and with 4-week exposures to ß-aminopropionitrile, an inhibitor of lysyl oxidase-mediated cross-linking of newly synthesized elastic and collagen fibers. RESULTS: We found a strong ß-aminopropionitrile-associated sexual dimorphism in aortic dilatation in Marfan mice and aortic rupture in wild-type mice, with dilatation correlating with compromised elastic fiber integrity and rupture correlating with compromised collagen fibril organization. A lower incidence of rupture of ß-aminopropionitrile-exposed Marfan aortas associated with increased lysyl oxidase, suggesting a compensatory remodeling of collagen that slows disease progression in the otherwise compromised Fbn1C1041G/+ aorta. CONCLUSIONS: Collagen fiber structure and function in the Marfan aorta are augmented, in part, by increased lysyl oxidase in female and especially male mice, which improves structural integrity, particularly via fibrils in the adventitia. Preserving or promoting collagen cross-linking may represent a therapeutic target for an otherwise vulnerable aorta.

FN (Fibronectin)-Integrin α5 Signaling Promotes Thoracic Aortic Aneurysm in a Mouse Model of Marfan Syndrome.

BACKGROUND: Marfan syndrome, caused by mutations in the gene for fibrillin-1, leads to thoracic aortic aneurysms (TAAs). Phenotypic modulation of vascular smooth muscle cells (SMCs) and ECM (extracellular matrix) remodeling are characteristic of both nonsyndromic and Marfan aneurysms. The ECM protein FN (fibronectin) is elevated in the tunica media of TAAs and amplifies inflammatory signaling in endothelial and SMCs through its main receptor, integrin α5ß1. We investigated the role of integrin α5-specific signals in Marfan mice in which the cytoplasmic domain of integrin α5 was replaced with that of integrin α2 (denoted α5/2 chimera). METHODS: We crossed α5/2 chimeric mice with Fbn1mgR/mgR mice (mgR model of Marfan syndrome) to evaluate the survival rate and pathogenesis of TAAs among wild-type, α5/2, mgR, and α5/2 mgR mice. Further biochemical and microscopic analysis of porcine and mouse aortic SMCs investigated molecular mechanisms by which FN affects SMCs and subsequent development of TAAs. RESULTS: FN was elevated in the thoracic aortas from Marfan patients, in nonsyndromic aneurysms, and in mgR mice. The α5/2 mutation greatly prolonged survival of Marfan mice, with improved elastic fiber integrity, mechanical properties, SMC density, and SMC contractile gene expression. Furthermore, plating of wild-type SMCs on FN decreased contractile gene expression and activated inflammatory pathways whereas α5/2 SMCs were resistant. These effects correlated with increased NF-kB activation in cultured SMCs and mgR aortas, which was alleviated by the α5/2 mutation or NF-kB inhibition. CONCLUSIONS: FN-integrin α5 signaling is a significant driver of TAA in the mgR mouse model. This pathway thus warrants further investigation as a therapeutic target.

VEuPathDB: the eukaryotic pathogen, vector and host bioinformatics resource center.

The Eukaryotic Pathogen, Vector and Host Informatics Resource (VEuPathDB, https://veupathdb.org) represents the 2019 merger of VectorBase with the EuPathDB projects. As a Bioinformatics Resource Center funded by the National Institutes of Health, with additional support from the Welllcome Trust, VEuPathDB supports >500 organisms comprising invertebrate vectors, eukaryotic pathogens (protists and fungi) and relevant free-living or non-pathogenic species or hosts. Designed to empower researchers with access to Omics data and bioinformatic analyses, VEuPathDB projects integrate >1700 pre-analysed datasets (and associated metadata) with advanced search capabilities, visualizations, and analysis tools in a graphic interface. Diverse data types are analysed with standardized workflows including an in-house OrthoMCL algorithm for predicting orthology. Comparisons are easily made across datasets, data types and organisms in this unique data mining platform. A new site-wide search facilitates access for both experienced and novice users. Upgraded infrastructure and workflows support numerous updates to the web interface, tools, searches and strategies, and Galaxy workspace where users can privately analyse their own data. Forthcoming upgrades include cloud-ready application architecture, expanded support for the Galaxy workspace, tools for interrogating host-pathogen interactions, and improved interactions with affiliated databases (ClinEpiDB, MicrobiomeDB) and other scientific resources, and increased interoperability with the Bacterial & Viral BRC.

Remodeling of Murine Branch Pulmonary Arteries Under Chronic Hypoxia and Short-Term Normoxic Recovery.

Chronic hypoxia plays a central role in diverse pulmonary pathologies, but its effects on longitudinal changes in the biomechanical behavior of proximal pulmonary arteries remain poorly understood. Similarly, effects of normoxic recovery have not been well studied. Here, we report hypoxia-induced changes in composition, vasoactivity, and passive biaxial mechanics in the main branch pulmonary artery of male C57BL/6J mice exposed to 10% FiO2 for 1, 2, or 3 weeks. We observed significant changes in extracellular matrix, and consequently wall mechanics, as early as 1 week of hypoxia. While circumferential stress and stiffness returned toward normal values by 2-3 weeks of hypoxia, area fractions of cytoplasm and thin collagen fibers did not return toward normal until after 1 week of normoxic recovery. By contrast, elastic energy storage and overall distensibility remained reduced after 3 weeks of hypoxia as well as following 1 week of normoxic recovery. While smooth muscle and endothelial cell responses were attenuated under hypoxia, smooth muscle but not endothelial cell responses recovered following 1 week of subsequent normoxia. Collectively, these data suggest that homeostatic processes were unable to preserve or restore overall function, at least over a brief period of normoxic recovery. Longitudinal changes are critical in understanding large pulmonary artery remodeling under hypoxia, and its reversal, and will inform predictive models of vascular adaptation.

Arterial Stiffness and Cardiovascular Risk in Hypertension.

Arterial stiffness, a leading marker of risk in hypertension, can be measured at material or structural levels, with the latter combining effects of the geometry and composition of the wall, including intramural organization. Numerous studies have shown that structural stiffness predicts outcomes in models that adjust for conventional risk factors. Elastic arteries, nearer to the heart, are most sensitive to effects of blood pressure and age, major determinants of stiffness. Stiffness is usually considered as an index of vascular aging, wherein individuals excessively affected by risk factor exposure represent early vascular aging, whereas those resistant to risk factors represent supernormal vascular aging. Stiffness affects the function of the brain and kidneys by increasing pulsatile loads within their microvascular beds, and the heart by increasing left ventricular systolic load; excessive pressure pulsatility also decreases diastolic pressure, necessary for coronary perfusion. Stiffness promotes inward remodeling of small arteries, which increases resistance, blood pressure, and in turn, central artery stiffness, thus creating an insidious feedback loop. Chronic antihypertensive treatments can reduce stiffness beyond passive reductions due to decreased blood pressure. Preventive drugs, such as lipid-lowering drugs and antidiabetic drugs, have additional effects on stiffness, independent of pressure. Newer anti-inflammatory drugs also have blood pressure independent effects. Reduction of stiffness is expected to confer benefit beyond the lowering of pressure, although this hypothesis is not yet proven. We summarize different steps for making arterial stiffness measurement a keystone in hypertension management and cardiovascular prevention as a whole.

G2Φnet: Relating genotype and biomechanical phenotype of tissues with deep learning.

Many genetic mutations adversely affect the structure and function of load-bearing soft tissues, with clinical sequelae often responsible for disability or death. Parallel advances in genetics and histomechanical characterization provide significant insight into these conditions, but there remains a pressing need to integrate such information. We present a novel genotype-to-biomechanical phenotype neural network (G2Φnet) for characterizing and classifying biomechanical properties of soft tissues, which serve as important functional readouts of tissue health or disease. We illustrate the utility of our approach by inferring the nonlinear, genotype-dependent constitutive behavior of the aorta for four mouse models involving defects or deficiencies in extracellular constituents. We show that G2Φnet can infer the biomechanical response while simultaneously ascribing the associated genotype by utilizing limited, noisy, and unstructured experimental data. More broadly, G2Φnet provides a powerful method and a paradigm shift for correlating genotype and biomechanical phenotype quantitatively, promising a better understanding of their interplay in biological tissues.

Evolving Mural Defects, Dilatation, and Biomechanical Dysfunction in Angiotensin II-Induced Thoracic Aortopathies.

BACKGROUND: Thoracic aortopathy associates with extracellular matrix remodeling and altered biomechanical properties. We sought to quantify the natural history of thoracic aortopathy in a common mouse model and to correlate measures of wall remodeling such as aortic dilatation or localized mural defects with evolving microstructural composition and biomechanical properties of the wall. METHODS: We combined a high-resolution multimodality imaging approach (panoramic digital image correlation and optical coherence tomography) with histopathologic examinations and biaxial mechanical testing to correlate spatially, for the first time, macroscopic mural defects and medial degeneration within the ascending aorta with local changes in aortic wall composition and mechanical properties. RESULTS: Findings revealed strong correlations between local decreases in elastic energy storage and increases in circumferential material stiffness with increasing proximal aortic diameter and especially mural defect size. Mural defects tended to exhibit a pronounced biomechanical dysfunction that is driven by an altered organization of collagen and elastic fibers. CONCLUSIONS: While aneurysmal dilatation is often observed within particular segments of the aorta, dissection and rupture initiate as highly localized mechanical failures. We show that wall composition and material properties are compromised in regions of local mural defects, which further increases the dilatation and overall structural vulnerability of the wall. Identification of therapies focused on promoting robust collagen accumulation may protect the wall from these vulnerabilities and limit the incidence of dissection and rupture.

A Fast, Robust Method for Quantitative Assessment of Collagen Fibril Architecture from Transmission Electron Micrographs.

Collagen is the most abundant protein in mammals; it exhibits a hierarchical organization and provides structural support to a wide range of soft tissues, including blood vessels. The architecture of collagen fibrils dictates vascular stiffness and strength, and changes therein can contribute to disease progression. While transmission electron microscopy (TEM) is routinely used to examine collagen fibrils under normal and pathological conditions, computational tools that enable fast and minimally subjective quantitative assessment remain lacking. In the present study, we describe a novel semi-automated image processing and statistical modeling pipeline for segmenting individual collagen fibrils from TEM images and quantifying key metrics of interest, including fibril cross-sectional area and aspect ratio. For validation, we show first-of-their-kind illustrative results for adventitial collagen in the thoracic aorta from three different mouse models.

A Fluid-Solid-Growth Solver for Cardiovascular Modeling.

We implement full, three-dimensional constrained mixture theory for vascular growth and remodeling into a finite element fluid-structure interaction (FSI) solver. The resulting "fluid-solid-growth" (FSG) solver allows long term, patient-specific predictions of changing hemodynamics, vessel wall morphology, tissue composition, and material properties. This extension from short term (FSI) to long term (FSG) simulations increases clinical relevance by enabling mechanobioloigcally-dependent studies of disease progression in complex domains.

Role of Axl in target organ inflammation and damage due to hypertensive aortic remodeling.

We have shown that excessive endothelial cell stretch causes release of growth arrest-specific 6 (GAS6), which activates the tyrosine kinase receptor Axl on monocytes and promotes immune activation and inflammation. We hypothesized that GAS6/Axl blockade would reduce renal and vascular inflammation and lessen renal dysfunction in the setting of chronic aortic remodeling. We characterized a model of aortic remodeling in mice following a 2-wk infusion of angiotensin II (ANG II). These mice had chronically increased pulse wave velocity, and their aortas demonstrated increased mural collagen. Mechanical testing revealed a marked loss of Windkessel function that persisted for 6 mo following ANG II infusion. Renal function studies showed a reduced ability to excrete a volume load, a progressive increase in albuminuria, and tubular damage as estimated by periodic acid Schiff staining. Treatment with the Axl inhibitor R428 beginning 2 mo after ANG II infusion had a minimal effect on aortic remodeling 2 mo later but reduced the infiltration of T cells, γ/δ T cells, and macrophages into the aorta and kidney and improved renal excretory capacity, reduced albuminuria, and reduced evidence of renal tubular damage. In humans, circulating Axl+/Siglec6+ dendritic cells and phospho-Axl+ cells correlated with pulse wave velocity and aortic compliance measured by transesophageal echo, confirming chronic activation of the GAS6/Axl pathway. We conclude that brief episodes of hypertension induce chronic aortic remodeling, which is associated with persistent low-grade inflammation of the aorta and kidneys and evidence of renal dysfunction. These events are mediated at least in part by GAS6/Axl signaling and are improved with Axl blockade.NEW & NOTEWORTHY In this study, a brief, 2-wk period of hypertension in mice led to progressive aortic remodeling, an increase in pulse wave velocity, and evidence of renal injury, dysfunction, and albuminuria. This end-organ damage was associated with persistent renal and aortic infiltration of CD8+ and γ/δ T cells. We show that this inflammatory response is likely due to GAS6/Axl signaling and can be ameliorated by blocking this pathway. We propose that the altered microvascular mechanical forces caused by increased pulse wave velocity enhance GAS6 release from the endothelium, which in turn activates Axl on myeloid cells, promoting the end-organ damage associated with aortic stiffening.

Vascular Mechanobiology: Homeostasis, Adaptation, and Disease.

Cells of the vascular wall are exquisitely sensitive to changes in their mechanical environment. In healthy vessels, mechanical forces regulate signaling and gene expression to direct the remodeling needed for the vessel wall to maintain optimal function. Major diseases of arteries involve maladaptive remodeling with compromised or lost homeostatic mechanisms. Whereas homeostasis invokes negative feedback loops at multiple scales to mediate mechanobiological stability, disease progression often occurs via positive feedback that generates mechanobiological instabilities. In this review, we focus on the cell biology, wall mechanics, and regulatory pathways associated with arterial health and how changes in these processes lead to disease. We discuss how positive feedback loops arise via biomechanical and biochemical means. We conclude that inflammation plays a central role in overriding homeostatic pathways and suggest future directions for addressing therapeutic needs.

Roles of mTOR in thoracic aortopathy understood by complex intracellular signaling interactions.

Thoracic aortopathy-aneurysm, dissection, and rupture-is increasingly responsible for significant morbidity and mortality. Advances in medical genetics and imaging have improved diagnosis and thus enabled earlier prophylactic surgical intervention in many cases. There remains a pressing need, however, to understand better the underlying molecular and cellular mechanisms with the hope of finding robust pharmacotherapies. Diverse studies in patients and mouse models of aortopathy have revealed critical changes in multiple smooth muscle cell signaling pathways that associate with disease, yet integrating information across studies and models has remained challenging. We present a new quantitative network model that includes many of the key smooth muscle cell signaling pathways and validate the model using a detailed data set that focuses on hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and its inhibition using rapamycin. We show that the model can be parameterized to capture the primary experimental findings both qualitatively and quantitatively. We further show that simulating a population of cells by varying receptor reaction weights leads to distinct proteomic clusters within the population, and that these clusters emerge due to a bistable switch driven by positive feedback in the PI3K/AKT/mTOR signaling pathway.

Comment on "Tensional homeostasis at different length scales" by D. Stamenovic and M. L. Smith, Soft Matter, 2021, 17, 10274-10285, DOI: 10.1039/D0SM01911A.

Many cell-types that reside within load bearing tissues appear to exhibit mechanical homeostasis, that is, a tendency to regulate particular mechanical quantities near a preferred value, often called a set-point. It is suggested here that assessing potential mechanical homeostasis requires careful attention to derivations and definitions, that is, appropriate solutions to the initial-boundary value problems that define the biophysical situation of interest and appropriate definitions of what is meant by homeostasis. Noting that this term was coined carefully, with homeo meaning "similar to" in contrast to homo meaning "the same as", one must be careful not only to identify the key mechano-regulated quantity (e.g., a stress rather than a flow or a force) but also the tolerance that defines the range of regulation, noting too that the specific target value of that variable may differ from region to region within the body while yet being regulated locally. Herein, we present a few examples to highlight specific derivations and definitions of importance when studying mechanical homeostasis across scales.

Inhibition of HIPK2 Alleviates Thoracic Aortic Disease in Mice With Progressively Severe Marfan Syndrome.

Objective: Despite considerable research, the goal of finding nonsurgical remedies against thoracic aortic aneurysm and acute aortic dissection remains elusive. We sought to identify a novel aortic PK (protein kinase) that can be pharmacologically targeted to mitigate aneurysmal disease in a well-established mouse model of early-onset progressively severe Marfan syndrome (MFS). Approach and Results: Computational analyses of transcriptomic data derived from the ascending aorta of MFS mice predicted a probable association between thoracic aortic aneurysm and acute aortic dissection development and the multifunctional, stress-activated HIPK2 (homeodomain-interacting protein kinase 2). Consistent with this prediction, Hipk2 gene inactivation significantly extended the survival of MFS mice by slowing aneurysm growth and delaying transmural rupture. HIPK2 also ranked among the top predicted PKs in computational analyses of DEGs (differentially expressed genes) in the dilated aorta of 3 MFS patients, which strengthened the clinical relevance of the experimental finding. Additional in silico analyses of the human and mouse data sets identified the TGF (transforming growth factor)-ß/Smad3 signaling pathway as a potential target of HIPK2 in the MFS aorta. Chronic treatment of MFS mice with an allosteric inhibitor of HIPK2-mediated stimulation of Smad3 signaling validated this prediction by mitigating thoracic aortic aneurysm and acute aortic dissection pathology and partially improving aortic material stiffness. Conclusions: HIPK2 is a previously unrecognized determinant of aneurysmal disease and an attractive new target for antithoracic aortic aneurysm and acute aortic dissection multidrug therapy.