Genomic regions associated with muscularity in beef cattle differ in five contrasting cattle breeds.

BACKGROUND: Linear type traits, which reflect the muscular characteristics of an animal, could provide insight into how, in some cases, morphologically very different animals can yield the same carcass weight. Such variability may contribute to differences in the overall value of the carcass since primal cuts vary greatly in price; such variability may also hinder successful genome-based association studies. Therefore, the objective of our study was to identify genomic regions that are associated with five muscularity linear type traits and to determine if these significant regions are common across five different breeds. Analyses were carried out using linear mixed models on imputed whole-genome sequence data in each of the five breeds, separately. Then, the results of the within-breed analyses were used to conduct an across-breed meta-analysis per trait. RESULTS: We identified many quantitative trait loci (QTL) that are located across the whole genome and associated with each trait in each breed. The only commonality among the breeds and traits was a large-effect pleiotropic QTL on BTA2 that contained the MSTN gene, which was associated with all traits in the Charolais and Limousin breeds. Other plausible candidate genes were identified for muscularity traits including PDE1A, PPP1R1C and multiple collagen and HOXD genes. In addition, associated (gene ontology) GO terms and KEGG pathways tended to differ between breeds and between traits especially in the numerically smaller populations of Angus, Hereford, and Simmental breeds. Most of the SNPs that were associated with any of the traits were intergenic or intronic SNPs located within regulatory regions of the genome. CONCLUSIONS: The commonality between the Charolais and Limousin breeds indicates that the genetic architecture of the muscularity traits may be similar in these breeds due to their similar origins. Conversely, there were vast differences in the QTL associated with muscularity in Angus, Hereford, and Simmental. Knowledge of these differences in genetic architecture between breeds is useful to develop accurate genomic prediction equations that can operate effectively across breeds. Overall, the associated QTL differed according to trait, which suggests that breeding for a morphologically different (e.g. longer and wider versus shorter and smaller) more efficient animal may become possible in the future.

Genetic control of temperament traits across species: association of autism spectrum disorder risk genes with cattle temperament.

BACKGROUND: Temperament traits are of high importance across species. In humans, temperament or personality traits correlate with psychological traits and psychiatric disorders. In cattle, they impact animal welfare, product quality and human safety, and are therefore of direct commercial importance. We hypothesized that genetic factors that contribute to variation in temperament among individuals within a species will be shared between humans and cattle. Using imputed whole-genome sequence data from 9223 beef cattle from three cohorts, a series of genome-wide association studies was undertaken on cattle flight time, a temperament phenotype measured as the time taken for an animal to cover a short-fixed distance after release from an enclosure. We also investigated the association of cattle temperament with polymorphisms in bovine orthologs of risk genes for neuroticism, schizophrenia, autism spectrum disorders (ASD), and developmental delay disorders in humans. RESULTS: Variants with the strongest associations were located in the bovine orthologous region that is involved in several behavioural and cognitive disorders in humans. These variants were also partially validated in independent cattle cohorts. Genes in these regions (BARHL2, NDN, SNRPN, MAGEL2, ABCA12, KIFAP3, TOPAZ1, FZD3, UBE3A, and GABRA5) were enriched for the GO term neuron migration and were differentially expressed in brain and pituitary tissues in humans. Moreover, variants within 100 kb of ASD susceptibility genes were associated with cattle temperament and explained 6.5% of the total additive genetic variance in the largest cattle cohort. The ASD genes with the most significant associations were GABRB3 and CUL3. Using the same 100 kb window, a weak association was found with polymorphisms in schizophrenia risk genes and no association with polymorphisms in neuroticism and developmental delay disorders risk genes. CONCLUSIONS: Our analysis showed that genes identified in a meta-analysis of cattle temperament contribute to neuron development functions and are differentially expressed in human brain tissues. Furthermore, some ASD susceptibility genes are associated with cattle temperament. These findings provide evidence that genetic control of temperament might be shared between humans and cattle and highlight the potential for future analyses to leverage results between species.

A Standardized Oxytocin Administration Protocol After Delivery to Reduce the Treatment of Postpartum Hemorrhage.

BACKGROUND: Postpartum hemorrhage (PPH) is a leading cause of maternal death, and its rate and severity have been increasing. Oxytocin is widely recommended for PPH prophylaxis, but consensus is lacking on the dose or duration, leading to disparate and subjective practices. In this study, clinical outcomes were compared before and after introduction of a quality measure: a standardized oxytocin protocol for PPH prophylaxis. METHODS: A retrospective cohort study was conducted of postpartum women ≥24 weeks' gestation delivered from 2010 to 2015. Women were grouped according to delivery pre-protocol (PREP) or post-protocol (POSTP) then subgrouped by specified criteria indicating low risk for PPH. The protocol was standardized for all POSTP women: 60 units of oxytocin over 5.25 hours postdelivery. The primary outcome was a composite: defined treatment for hemorrhage or uterine atony. RESULTS: Of 16,811 women included, 46.3% were PREP (n = 7,791), and 53.7% were POSTP (n = 9,020). A total of 2,315 subjects (13.8%) met low risk for PPH criteria. The primary outcome rate was lower after protocol introduction for all subjects (7.0% vs. 4.6%; p <0.001) and low-risk subset women (3.8% vs. 1.4%; p <0.001). Delivery after protocol introduction was associated with a decreased risk of the primary outcome among all subjects women (adjusted odds ratio [AOR], 0.63; 95% confidence interval [CI] = 0.55-0.72) and low-risk subset women (AOR, 0.33; 95% CI = 0.19-0.57). CONCLUSION: Standardized, higher-dose postpartum oxytocin may be associated with less PPH treatment in this cohort. These findings support standardization and set the stage for a randomized controlled trial.

Constructing Health State Descriptions for Low-Risk Thyroid Cancer: Stakeholder Engagement and Formative Qualitative Research.

OVERVIEW: This paper describes stakeholder involvement and formative qualitative research in the creation of health state descriptions (HSDs) or vignettes for low-risk thyroid cancer. The aim of this project was to engage stakeholders in the contribution of a novel set of HSDs, an important first step in the process of assessing value in thyroid cancer health states. METHODS: We draw upon formative, descriptive qualitative methods, following a multi-stage framework of data collection. We conducted individual semi-structured interviews, cognitive interviews, and focus groups with thyroid cancer patients, community providers, academic subspecialists, and participants with no thyroid cancer diagnosis (N = 31). The HSDs went through several iterations over the course of a year, in collaboration with a highly engaged community advisory board, laying the groundwork for HSDs that are comprehensible, comparable, and appropriate for stated-preference research. FINDINGS: Thyroid cancer survivors compared their experiences with those described in the HSDs. Feedback included concern for the emotional well-being of study participants who would be reading them. Providers were attuned to the need for clinical accuracy and made suggestions to reflect their clinical experience, including for patients with complications or disease progression. The pilot participants with no thyroid cancer were particularly valuable in promoting the need to simplify language and maximize readability. DISCUSSION: Stakeholder engagement was critical to being responsive to feedback as the iterations were refined and presented. Continuous engagement and consultation with multiple sources strengthened the HSDs. A secondary outcome from this project is that stakeholders expressed interest in adapting the HSDs into decision aids for people newly diagnosed with low-risk thyroid cancer.

Identification of a mechanism underlying regulation of the anti-angiogenic forkhead transcription factor FoxO1 in cultured endothelial cells and ischemic muscle.

Chronic limb ischemia, a complication commonly observed in conjunction with cardiovascular disease, is characterized by insufficient neovascularization despite the up-regulation of pro-angiogenic mediators. One hypothesis is that ischemia induces inhibitory signals that circumvent the normal capillary growth response. FoxO transcription factors exert anti-proliferative and pro-apoptotic effects on many cell types. We studied the regulation of FoxO1 protein in ischemic rat skeletal muscle following iliac artery ligation and in cultured endothelial cells. We found that FoxO1 expression was increased in capillaries within ischemic muscles compared with those from rats that underwent a sham operation. This finding correlated with increased expression of p27(Kip1) and reduced expression of Cyclin D1. Phosphorylated Akt was reduced concurrently with the increase in FoxO1 protein. In skeletal muscle endothelial cells, nutrient stress as well as lack of shear stress stabilized FoxO1 protein, whereas shear stress induced FoxO1 degradation. Endogenous FoxO1 co-precipitated with the E3 ubiquitin ligase murine double minute-2 (Mdm2) in endothelial cells, and this interaction varied in direct relation to the extent of Akt and Mdm2 phosphorylation. Moreover, ischemic muscles had a decreased level of Mdm2 phosphorylation and a reduced interaction between Mdm2 and FoxO1. Our results provide novel evidence that the Akt-Mdm2 pathway acts to regulate endothelial cell FoxO1 expression and illustrate a potential mechanism underlying the pathophysiological up-regulation of FoxO1 under ischemic conditions.

An overview of international genetic evaluations of show jumping in sport horses.

The breeding of sport horses to compete in the Olympic disciplines of show jumping, eventing, and dressage is fast becoming a global industry with the increased use of reproductive technologies, including artificial insemination and embryo transfer. Reproductive technologies have facilitated the dissemination of genetics from elite horses across multiple countries and breeds as breeders are no longer limited by location. Due to this increased level of crossbreeding, there is an increased need for estimated breeding values (EBVs) for sport horse performance that can be compared across breeds and countries. However, the implementation of across-breed or across-country genetic evaluations has been limited by the differences in each studbook's individual breeding programs and genetic evaluations. Consequently, the aim of this review was to compare the genetic evaluations for show jumping of sport horse studbooks worldwide. The top sport horse studbooks in the world according to the World Breeding Federation for Sport Horses Studbook Rankings 2019 were contacted by email to request information on their current breeding programs and genetic evaluations. Twenty-six of the 51 studbooks contacted replied to this request but only 18 of these studbooks conducted their own genetic evaluations or were part of a larger genetic evaluation in their country of origin. The other eight studbooks were not involved in genetic evaluations at present but expressed an interest in the implementation of such in the future. Overall, many differences were identified among the genetic evaluations of each studbook or each country. The definition of show jumping performance differed within each evaluation and the methods and models utilized also differed. Despite some stallions and mares being registered in multiple studbooks or having progeny in multiple studbooks, these differences make comparison of EBVs across studbooks difficult. Further transparency and collaboration of sport horse studbooks with organizations such as Interstallion, will be essential to facilitate any future implementation of international genetic evaluations for show jumping performance.

Identification of genomic regions that exhibit sexual dimorphism for size and muscularity in cattle.

Sexual dimorphism, the phenomenon whereby males and females of the same species are distinctive in some aspect of appearance or size, has previously been documented in cattle for traits such as growth rate and carcass merit using a quantitative genetics approach. No previous study in cattle has attempted to document sexual dimorphism at a genome level; therefore, the objective of the present study was to determine whether genomic regions associated with size and muscularity in cattle exhibited signs of sexual dimorphism. Analyses were undertaken on 10 linear-type traits that describe the muscular and skeletal characteristics of both males and females of five beef cattle breeds: 1,444 Angus (AA), 6,433 Charolais (CH), 1,129 Hereford, 8,745 Limousin (LM), and 1,698 Simmental. Genome-wide association analyses were undertaken using imputed whole-genome sequence data for each sex separately by breed. For each single-nucleotide polymorphism (SNP) that was segregating in both sexes, the difference between the allele substitution effect sizes for each sex, in each breed separately, was calculated. Suggestively (P ≤ 1 × 10-5) sexually dimorphic SNPs that were segregating in both males and females were detected for all traits in all breeds, although the location of these SNPs differed by both trait and breed. Significantly (P ≤ 1 × 10-8) dimorphic SNPs were detected in just three traits in the AA, seven traits in the CH, and three traits in the LM. The vast majority of all segregating autosomal SNPs (86% in AA to 94% in LM) had the same minor allele in both males and females. Differences (P ≤ 0.05) in allele frequencies between the sexes were observed for between 36% (LM) and 66% (AA) of the total autosomal SNPs that were segregating in both sexes. Dimorphic SNPs were located within a number of genes related to muscularity and/or size including the NAB1, COL5A2, and IWS1 genes on BTA2 that are located close to, and thought to be co-inherited with, the MSTN gene. Overall, sexual dimorphism exists in cattle at the genome level, but it is not consistent by either trait or breed.

The angiogenic response to skeletal muscle overload is not dependent on mast cell activation.

OBJECTIVE: To determine if mast cell activation in skeletal muscle contributes to overload-induced angiogenesis. METHODS: Extensor digitorum longus muscle was overloaded through extirpation of the synergist muscle tibialis anterior. Muscles were removed after 1, 2, 4, 7 or 14 days, and mast cell density and degranulation were quantified by histology. The mast cell stabilizer, cromolyn, was administered acutely or chronically to test if mast cell degranulation contributes to overload-induced angiogenesis. Angiogenesis was determined by calculating capillary to muscle Fiber ratio; mast cell density and activation were quantified by histology, MMP-2 levels were assessed by gelatin zymography and VEGF protein levels were assessed by Western blotting. RESULTS: Muscle overload increased mast cell degranulation and total mast cell number within 7 days. Mast cell stabilization with cromolyn attenuated degranulation but did not inhibit the increased mast cell density, MMP-2 activity, VEGF protein levels or the increase in capillary number following muscle overload. CONCLUSIONS: Mast cell degranulation and accumulation precede overload-induced angiogenesis, but mast cell activation is not critical to the angiogenic response following skeletal muscle overload.

Genomic Regions Associated With Skeletal Type Traits in Beef and Dairy Cattle Are Common to Regions Associated With Carcass Traits, Feed Intake and Calving Difficulty.

Linear type traits describing the skeletal characteristics of an animal are moderately to strongly genetically correlated with a range of other performance traits in cattle including feed intake, reproduction traits and carcass merit; thus, type traits could also provide useful insights into the morphological differences among animals underpinning phenotypic differences in these complex traits. The objective of the present study was to identify genomic regions associated with five subjectively scored skeletal linear traits, to determine if these associated regions are common in multiple beef and dairy breeds, and also to determine if these regions overlap with those proposed elsewhere to be associated with correlated performance traits. Analyses were carried out using linear mixed models on imputed whole genome sequence data separately in 1,444 Angus, 1,129 Hereford, 6,433 Charolais, 8,745 Limousin, 1,698 Simmental, and 4,494 Holstein-Friesian cattle, all scored for the linear type traits. There was, on average, 18 months difference in age at assessment of the beef versus the dairy animals. While the majority of the identified quantitative trait loci (QTL), and thus genes, were both trait-specific and breed-specific, a large-effect pleiotropic QTL on BTA6 containing the NCAPG and LCORL genes was associated with all skeletal traits in the Limousin population and with wither height in the Angus. Other than that, little overlap existed in detected QTLs for the skeletal type traits in the other breeds. Only two QTLs overlapped the beef and dairy breeds; both QTLs were located on BTA5 and were associated with height in both the Angus and the Holstein-Friesian, despite the difference in age at assessment. Several detected QTLs in the present study overlapped with QTLs documented elsewhere that are associated with carcass traits, feed intake, and calving difficulty. While most breeding programs select for the macro-traits like carcass weight, carcass conformation, and feed intake, the higher degree of granularity with selection on the individual linear type traits in a multi-trait index underpinning the macro-level goal traits, presents an opportunity to help resolve genetic antagonisms among morphological traits in the pursuit of the animal with optimum performance metrics.

Differential role of beta-catenin in VEGF and histamine-induced MMP-2 production in microvascular endothelial cells.

Increases in endothelial cell permeability and production of matrix-degrading enzymes are two early steps in the angiogenic process. Factors such as vascular endothelial growth factor (VEGF) and histamine induce the angiogenic process through alterations in both permeability and proteolysis. We hypothesized that beta-catenin acts as a positive regulator of MMP-2 and MT1-MMP transcription following VEGF or histamine stimulation. Rat microvascular endothelial cells were exposed to VEGF or histamine overnight and MMP-2 protein production was assessed by gelatin zymography. Latent MMP-2 protein levels were increased following VEGF and histamine treatment as were MMP-2 mRNA transcript levels. Endothelial cells exposed to VEGF and histamine had an increased level of nuclear beta-catenin, which was sensitive to inhibition of the PI3-kinase signaling pathway. Promoter assays indicated increased transcriptional activity of both MMP-2 and MT1-MMP in endothelial cells co-transfected with luciferase reporter constructs and beta-catenin. Inhibition of beta-catenin signaling with inhibitor of catenin and T cell factor (ICAT) revealed that the VEGF-induced increase in MMP-2 mRNA is beta-catenin dependent. Interestingly, while MMP-2 mRNA levels increased in response to histamine H1 or H2 receptor activation, significantly larger increases were observed in cells co-treated with ICAT and histamine or the histamine receptor agonists, HTMT and dimaprit. While both VEGF and histamine increase nuclear beta-catenin and MMP-2 production, the role of beta-catenin in MMP-2 regulation differs between the two stimuli.

A Standardized Postpartum Oxytocin Protocol to Reduce Hemorrhage Treatment: Outcomes by Delivery Mode.

BACKGROUND: Postpartum hemorrhage prophylaxis guidelines lack consensus and do not address the major factor of delivery mode. This creates quality and safety concerns. The objective of this study was to evaluate the effect of implementing a standardized prophylaxis protocol on postpartum hemorrhage treatment by delivery mode. METHODS: A secondary analysis was conducted of all women ≥ 24 weeks' gestational age who delivered from January 2010 to June 2015 at one perinatal center. Women were grouped according to delivery pre-protocol (nonstandardized postpartum oxytocin) or post-protocol (standardized postpartum oxytocin). This retrospective cohort study compared outcomes by delivery mode. The primary outcome was treatment for postpartum hemorrhage or uterine atony. RESULTS: A total of 16,811 women were studied, stratified by three delivery modes: spontaneous vaginal (n = 10,542), operative vaginal (n = 963), and cesarean (n = 5,306). Delivery post-protocol introduction was associated with a lower treatment rate of postpartum hemorrhage for spontaneous vaginal (5.7% vs. 3.1%; p < 0.001) and cesarean (9.4% vs. 7.8%; p = 0.036) modes. Delivery post-protocol introduction was associated with a decreased risk of the primary composite outcome across all modes: spontaneous vaginal (adjusted odds ratio [AOR] = 0.537; 95% confidence interval [CI]: 0.442-0.653), operative vaginal (AOR = 0.490; 95% CI: 0.285-0.842), and cesarean (AOR = 0.812; 95% CI: 0.666-0.988). CONCLUSION: A standardized oxytocin protocol was associated with a lower postpartum hemorrhage treatment rate for cesarean and vaginal deliveries, but not for operative vaginal deliveries. The prophylactic effect of our higher dose protocol had the strongest benefit with women delivering vaginally.

Genetic covariance components within and among linear type traits differ among contrasting beef cattle breeds.

Linear type traits describing the skeletal, muscular, and functional characteristics of an animal are routinely scored on live animals in both the dairy and beef cattle industries. Previous studies have demonstrated that genetic parameters for certain performance traits may differ between breeds; no study, however, has attempted to determine if differences exist in genetic parameters of linear type traits among breeds or sexes. Therefore, the objective of the present study was to determine if genetic covariance components for linear type traits differed among five contrasting cattle breeds, and to also investigate if these components differed by sex. A total of 18 linear type traits scored on 3,356 Angus (AA), 31,049 Charolais (CH), 3,004 Hereford (HE), 35,159 Limousin (LM), and 8,632 Simmental (SI) were used in the analysis. Data were analyzed using animal linear mixed models which included the fixed effects of sex of the animal (except in the investigation into the presence of sexual dimorphism), age at scoring, parity of the dam, and contemporary group of herd-date of scoring. Differences (P < 0.05) in heritability estimates, between at least two breeds, existed for 13 out of 18 linear type traits. Differences (P < 0.05) also existed between the pairwise within-breed genetic correlations among the linear type traits. Overall, the linear type traits in the continental breeds (i.e., CH, LM, SI) tended to have similar heritability estimates to each other as well as similar genetic correlations among the same pairwise traits, as did the traits in the British breeds (i.e., AA, HE). The correlation between a linear function of breeding values computed conditional on covariance parameters estimated from the CH breed with a linear function of breeding values computed conditional on covariance parameters estimated from the other breeds was estimated. Replacing the genetic covariance components estimated in the CH breed with those of the LM had least effect but the impact was considerable when the genetic covariance components of the AA were used. Genetic correlations between the same linear type traits in the two sexes were all close to unity (≥0.90) suggesting little advantage in considering these as separate traits for males and females. Results for the present study indicate the potential increase in accuracy of estimated breeding value prediction from considering, at least, the British breed traits separate to continental breed traits.

Regulators of angiogenesis and strategies for their therapeutic manipulation.

Angiogenesis provides a mechanism by which delivery of oxygen and nutrients is adapted to compliment changes in tissue mass or metabolic activity. However, maladaptive angiogenesis is integral to the process of several diseases common in Western countries, including tumor growth, vascular insufficiency, diabetic retinopathy and rheumatoid arthritis. Understanding the process of capillary growth, including the identification and functional analyses of key pro- and anti-angiogenic factors, provides knowledge that can be applied to improve/reverse these pathological states. Initially, angiogenesis research focused predominantly on vascular endothelial growth factor (VEGF) as a main player in the angiogenesis cascade. It is apparent now that participation of multiple angiogenic factors and signal pathways is critical to enable effective growth and maturation of nascent capillaries. The purpose of this review is to focus on recent progress in identifying angiogenesis signaling pathways that show promise as targets for successful induction or inhibition of capillary growth. The strategies applied to achieve these contradictory tasks are discussed within the framework of our existing fundamental knowledge of angiogenesis signaling cascades, with an emphasis on comparing the employment of distinctive tactics in modulation of these pathways. Innovative developments that are presented include: (1) inducing a pleiotropic response via activation or inhibition of angiogenic transcription factors; (2) modulation of nitric oxide tissue concentration; (3) manipulating the kallikrein-kinin system; (4) use of endothelial progenitor cells as a means to either directly contribute to capillary growth or to be used as a vehicle to deliver "suicide genes" to tumor tissue.

Nursing peer review of late deceleration recognition and intervention to improve patient safety.

We describe a nurse peer-review process to improve late deceleration recognition and intervention on one labor and delivery unit. Monthly chart audits (n = 721) met the goal of 75% reviewer agreement after the 4th month of implementation and have been maintained to date. Nurses recognized for excellence were more likely to be certified, work day shift, or be a member of the Perinatal Safety Team. Institutional support, a dedicated review team, and education contributed to success.

Implementing an induction scheduling procedure and consent form to improve quality of care.

Inappropriate elective inductions of labor put patients at increased risk of cesarean, neonatal morbidity, and elevated cost. A scheduling procedure and consent form were implemented to eliminate elective induction at less than 39 weeks gestation and align indications for induction with American College of Obstetricians and Gynecologists guidelines. In 25 of the 28 months following implementation of the new process, we achieved the goal of eliminating elective induction of labor at less than 39 weeks gestation.

HIF-1alpha and HIF-2alpha play a central role in stretch-induced but not shear-stress-induced angiogenesis in rat skeletal muscle.

Angiogenesis, which is essential for the physiological adaptation of skeletal muscle to exercise, occurs in response to the mechanical forces of elevated capillary shear stress and cell stretch. Increased production of VEGF is a characteristic of endothelial cells undergoing either stretch- or shear-stress-induced angiogenesis. Because VEGF production is regulated by hypoxia inducible factors (HIFs), we examined whether HIFs play a significant role in the angiogenic process initiated by these mechanical forces. Rat extensor digitorum longus (EDL) muscles were overloaded to induce stretch, or exposed to the dilator prazosin to elevate capillary shear stress, and capillaries from these muscles were isolated by laser capture microdissection for RNA analysis. HIF-1alpha and HIF-2alpha transcript levels increased after 4 and 7 days of stretch, whereas a transient early induction of HIF-1alpha and HIF-2alpha transcripts was detected in capillaries from prazosin-treated muscles. Skeletal muscle microvascular endothelial cells exposed to 10% stretch in vitro showed an elevation in HIF-1alpha and HIF-2alpha mRNA, which was preceded by increases in HIF-binding activity. Conversely, HIF-1alpha and HIF-2alpha mRNA were reduced significantly, and HIF-alpha proteins were undetectable, after 24 h exposure to elevated shear stress (16 dyn cm(-2) (16 x10(-5) N cm(-2)). Given the disparate regulation of HIFs in response to these mechanical stimuli, we tested the requirement of HIF-alpha proteins in stretch- and shear-stress-induced angiogenesis by impeding HIF accumulation through use of the geldanamycin derivative 17-DMAG. Treatment with 17-DMAG significantly impaired stretch-induced, but not shear-stress-induced, angiogenesis. Together, these results illustrate that activation of HIF-1alpha and HIF-2alpha contributes significantly to stretch- but not to shear-stress-induced capillary growth.

Involvement of MMPs in the outward remodeling of collateral mesenteric arteries.

Persistent elevation in shear stress within conduit or resistance arteries causes structural luminal expansion, which serves to normalize shear stress while maintaining increased flow to the downstream vasculature. Although it is known that this adaptation involves cellular proliferation and remodeling of the extracellular matrix, the specific cellular events underlying these responses are poorly understood. Matrix metalloproteinases (MMPs) contribute to extensive remodeling of the extracellular matrix in conduit vessels and vein grafts exposed to high flow. However, involvement of MMPs in remodeling of small muscular collateral arteries, which are exposed to less severe increases in shear stress, has not been tested. We utilized an established model of outward remodeling in mesenteric collateral arteries to determine whether MMPs were upregulated during the remodeling response and to test whether MMP activity was required for luminal expansion. By 4 days, MMP-2 and membrane type 1 MMP (MT1-MMP), but not MMP-9, protein levels were significantly elevated in collateral arteries, as assessed by gelatin zymography and immunostaining. MMP-2 and MT1-MMP proteins, together with their respective transcriptional activators c-Jun and Egr-1 were localized predominantly to the smooth muscle layer of the collateral arteries. The general MMP inhibitor doxycycline prevented luminal expansion of collateral arteries but did not affect the endothelial cell proliferative or medial growth responses. In conclusion, this study provides evidence that MMP-2 and MT1-MMP are upregulated in collateral arteries exposed to elevated shear stress and that MMP activity is essential for the full remodeling response that leads to outward luminal expansion.