The association between symmetric dimethylarginine concentrations and various neoplasms in dogs and cats.

Following the introduction of the symmetric dimethylarginine (SDMA) immunoassay, cases were reported where the SDMA concentration was markedly increased above the reference interval (RI) with neither concurrent increases in serum creatinine (Cr) concentrations nor clinical signs of kidney disease. Many of these animals were also concurrently diagnosed with cancer, most commonly lymphoma. The purpose of the study was to evaluate the association of increased SDMA in dogs and cats with lymphoma and other cancers as compared with age- and breed-matched non-tumour controls. In this retrospective case-control study, serum chemistry results from 1804 tumour cases, and age- and breed-matched non-tumour control animals were used. Matched-pair odds ratios between animals diagnosed with neoplasms and non-tumour controls for dichotomized SDMA values were determined by tumour type. SDMA concentrations were significantly higher in dogs and cats with lymphoma (p < .0001) compared with non-tumour controls. The odds ratio for increased SDMA concentrations in dogs with lymphoma was 10.0 (95% CI, 5.98-16.72) and for cats with lymphoma was 3.04 (95% CI 1.95-4.73). A significant number of canine and feline lymphoma cases had an increased SDMA concentration not associated with an increased Cr concentration (p < .001). Canine and feline lymphoma patients have an increased odds of having a SDMA concentration above the RI at diagnosis. Further characterization and evaluation of dogs and cats with lymphoma is required to help understand the mechanism(s) and the clinical significance of these alterations.

Evaluation of renal injury and function biomarkers, including symmetric dimethylarginine (SDMA), in the rat passive Heymann nephritis (PHN) model.

Symmetric dimethylarginine (SDMA) is a serum biomarker of excretory renal function which consistently correlates with glomerular filtration rate (GFR) across multiple species including rats, dogs, and humans. In human and veterinary clinical settings SDMA demonstrates enhanced sensitivity for detection of declining renal function as compared to other serum biomarkers, but application in preclinical study designs thus far has been limited. The purpose of this study was to determine the performance of serum SDMA in a rat passive Heyman nephritis model of glomerulopathy. In addition to SDMA other biomarkers of excretory renal function were measured including serum creatinine (sCr), blood urea nitrogen (BUN), and cystatin C along with creatinine clearance. Urinary renal biomarkers including microalbumin (µALB), clusterin (CLU), cystatin C, kidney injury marker-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were also measured. PHN was induced using commercial sheep anti-Fx1A serum. Tissue, serum, and urine were collected from groups of control and anti-Fx1A-treated animals for biomarker evaluation, hematology, urinalysis, serum biochemistry, and histologic examination of kidney. Over the course of a 28-day study, concentrations of the urinary biomarkers µALB, CLU, cystatin C, NGAL, KIM-1 and the serum biomarker cystatin C increased significantly in anti-Fx1A-treated rats as compared to controls but no significant increase in serum SDMA, sCr, BUN, or creatinine clearance were noted in anti-Fx1A-treated rats. Given lack of direct GFR measurement or significant change in the renal function biomarkers sCr, BUN, and creatinine clearance, it is unclear if GFR differed significantly between control and anti-Fx1A-treated rats in this study, though urinary biomarkers and histopathologic findings supported renal injury in anti-Fx1A-treated rats over the time course investigated. This study is among the first to investigate serum SDMA in a rat model relevant to preclinical safety assessment and serves to inform future experimental designs and biomarker selection when evaluation of glomerular injury is of priority.

Evaluation of Renal Biomarkers, Including Symmetric Dimethylarginine, following Gentamicin-Induced Proximal Tubular Injury in the Rat.

Symmetric dimethylarginine (SDMA) is an excretory renal function biomarker shown to correlate well with glomerular filtration rate in dogs, cats, humans, and rats. The objectives of this study were to determine utility of serum SDMA as a renal biomarker in a rat model of gentamicin-induced renal injury and to provide validation of a commercially available SDMA immunoassay for rat serum. Rats were randomly assigned to one of three dose levels of gentamicin (20, 50, or 100 mg/kg) or a vehicle control group and dosed once daily by subcutaneous injection for either four or ten days. Serum and urine renal biomarker evaluation, including serum SDMA, hematologic and serum biochemical analysis, urinalysis, and histologic examination of kidney, were performed. Before biologic validation, analytic validation of the SDMA immunoassay for rat serum was performed, including assessment of assay accuracy, precision, analytical sensitivity, linearity, analyte stability, and interference testing. Among markers of excretory renal function, SDMA and serum creatinine increased earliest and at the lowest gentamicin concentrations and were significantly increased in both the 50- and 100- mg/kg dose levels in the four- and ten-dose treatment groups compared with controls. Time- and dose-dependent increases were noted for all urinary biomarkers investigated in this study, with microalbumin being most responsive and osteopontin least responsive for detection of gentamicin-induced injury across dose levels and schedules investigated. The SDMA immunoassay met all set quality requirements assessed in analytical validation. This study is the first to investigate performance of serum SDMA compared with other excretory renal function markers in a rat gentamicin acute toxicity model. In this study, serum SDMA was an earlier biomarker for detection of gentamicin-induced toxicity than serum cystatin C, BUN, and creatinine clearance. The SDMA immunoassay provides a reliable commercially available assay for future renal investigations in rat models.

A 3-year retrospective analysis of canine intestinal parasites: fecal testing positivity by age, U.S. geographical region and reason for veterinary visit.

BACKGROUND: Canine life stage is a key factor in parasite prevalence as clinical signs associated with parasitism are more common in pups. In adult dogs, health status and geographical region may also play a role in parasite prevalence. The purpose of this study was to evaluate fecal test results using zinc sulfate flotation by centrifugation combined with fecal antigen testing for hookworms (Ancylostoma spp. Uncinaria stenocephala), ascarids (Toxocara canis, Toxascaris spp., Baylisascaris spp.) and whipworms (Trichuris vulpis) sorted by age, geographical region and veterinary visit type. METHODS: A retrospective sample of intestinal parasite panels submitted to IDEXX Laboratories from 1,626,104 individual dogs were selected from the continental USA from 1 January 2017 to 31 December 2019. These data contain results from fecal exams performed using zinc sulfate flotation by centrifugation paired with coproantigen immunoassay results for hookworms, ascarids, whipworms and Giardia (Fecal Dx® with Giardia coproantigen immunoassay plate). For paired testing, if either the coproantigen assay or flotation test was positive, the sample was considered to be positive. Data were summarized by age category, U.S. Census Bureau geographical region (Northeast, South, Midwest, West) and veterinary visit type. Visit types were subdivided into Wellness Visits and Other Clinical Visits in which a fecal sample was submitted. RESULTS: In dogs presenting for either Wellness Visits or Other Clinical Visits in which Giardia testing was included, Giardia had the highest positivity (combined results for microscopy and coproantigen: 12.2 and 10.8%, respectively), followed by hookworms (combined microscopy and coproantigen: 4.1 and 4.2%, respectively), ascarids (combined microscopy and coproantigen: 2.5 and 1.7%, respectively) and whipworms (combined microscopy and coproantigen: 1.1 and 1.4%, respectively). When all test results were pooled together, pups aged 2-6 months were observed to have the highest proportion of positive results by either microscopy or coproantigen immunoassay regardless of clinical visit type. Parasite positivity varied by geographical region. Regardless of visit type, age or geographical region, the coproantigen method was observed to find a higher proportion of positive test results than microscopy in Giardia, ascarids, hookworms and whipworms. CONCLUSIONS: The Fecal Dx® coproantigen immunoassay combined with the zinc sulfate flotation by centrifugation method uncovers a higher number of positive hookworm, ascarid and whipworm infections than zinc sulfate flotation alone in both pups and adult dogs across all geographical regions of the USA regardless of visit type.

Risk of Development of Chronic Kidney Disease After Exposure to Borrelia burgdorferi and Anaplasma spp.

Lyme disease is a multi-faceted illness caused by infection due to Borrelia burgdorferi. Acute kidney damage secondary to Lyme disease is well described but less so as a chronic event. The role of Anaplasma spp. and secondary kidney dysfunction is not known. A retrospective cohort study was performed to determine if dogs within a defined Lyme disease and anaplasmosis region with B. burgdorferi or Anaplasma spp. antibodies had an increased risk of chronic kidney disease (CKD). Patient exposure was defined as having a B. burgdorferi or Anaplasma spp. antibody positive result recorded at any point in the available patient history. CKD was defined as concurrent increased symmetric dimethylarginine and creatinine (Cr) for a minimum of 25 days with inappropriate urine specific gravity (USG). Patients were matched using propensity scoring to control for age, region, and breed. Contingency tables were used to compare dogs seropositive and not seropositive to B. burgdorferi and Anaplasma spp. and CKD outcome. For each comparison that was performed, statistical significance was defined by a P-value of <.025. The risk ratio of CKD for patients exposed to B. burgdorferi and Anaplasma spp. were found to be 1.43 (95% confidence interval [CI, 1.27, 1.61], P < .0001) and 1.04, (95% CI [0.87, 1.24], P = .6485), respectively. Results suggest in this cohort no increased risk for developing CKD when exposed to Anaplasma spp. but a significant increase in risk for developing CKD with exposure to B. burgdorferi.

Retrospective analysis of feline intestinal parasites: trends in testing positivity by age, USA geographical region and reason for veterinary visit.

BACKGROUND: The goals of this retrospective study were to estimate parasite positivity in samples from cats using zinc sulfate fecal flotation by centrifugation ("centrifugation") and coproantigen and examine trends with age, geographical region and reason for visit to veterinarian. Common methods of parasite detection, such as centrifugal flotation, passive flotation, or direct smear, may underrepresent the true prevalence of intestinal parasites in cats. Coproantigen testing detects more positive samples than traditional methods alone. METHODS: Feline fecal test results from the continental USA containing results for fecal exams performed using centrifugation paired with coproantigen results for ascarid, hookworm, whipworm and Giardia were obtained from the database of a national commercial reference laboratory comprised of multiple regional sites. RESULTS: Parasite positivity was highest in samples from young cats and decreased with cat age. The western region of the USA had lower total parasite positivity than other regions for all parasites except Giardia. Cats receiving fecal tests during veterinary wellness visits had only slightly lower parasite positivity than samples from cats during sick clinical visits. CONCLUSIONS: This study showed a larger population of cats are at increased risk of parasitism than commonly believed and coproantigen testing produces more positive test results for the four parasites that antigen can detect than centrifugation of feline fecal samples.

Association between breed and renal biomarkers of glomerular filtration rate in dogs.

BACKGROUND: Kidney disease, especially chronic kidney disease (CKD), is common in older dogs. The biomarkers symmetric dimethylarginine (SDMA) and creatinine (Cr) are indicators of glomerular filtration rate (GFR). This retrospective study used these biomarkers to identify groups at risk of decreased GFR at the breed level. METHODS: Data from dogs with a single serum chemistry result that included Cr and SDMA submitted between July 2015 through December 2017 were included. Dogs were identified by breed and age group. Decreased GFR was defined as Cr above 1.9 mg/dl or SDMA above 18 µg/dl. RESULTS: Fourteen breeds had a significantly higher percentage of dogs with increased SDMA or Cr for one or more age groups. Geriatric and senior Shetland sheepdogs, Yorkshire terriers and Pomeranians were significantly more likely to have increased renal biomarkers. Boxers were identified with significantly increased renal biomarkers in the age groups spanning two months to 10 years of age. CONCLUSION: Evidence of decreased GFR occurred commonly in older dogs of most breeds, especially geriatric dogs greater than 10 years of age, but there were some exceptions, with more significant changes affecting younger animals of several breeds. The combination of SDMA and Cr identified more cases of decreased GFR than either SDMA or Cr alone.

Association Between Exposure to Ehrlichia spp. and Risk of Developing Chronic Kidney Disease in Dogs.

Ehrlichiosis is a common vector-borne disease caused by Ehrlichia spp. This retrospective matched cohort study was performed to determine if dogs with Ehrlichia spp. antibodies had an increased incidence of chronic kidney disease (CKD). Exposure to Ehrlichia spp. was defined as having an Ehrlichia spp. antibody-positive result recorded at any point in their available patient history. The outcome of CKD was defined as concurrent increased symmetric dimethylarginine (>14 µg/dL) and creatinine (>1.5 mg/dL) for a minimum of 25 days with inappropriate urine specific gravity (<1.030). Patients were matched using propensity score matching to control for age, geography, and breed. A total of 22,440 patients and controls in E canis-endemic regions of the United States were used in this analysis. Contingency tables were used to compare dogs with and without exposure to Ehrlichia spp.-infected ticks and CKD outcome. The relative risk of CKD for patients exposed to ticks carrying Ehrlichia spp. was found to be 2.12 (95% confidence interval [1.35-3.15], p < 0.0006). This study identified that testing positive for Ehrlichia spp. antibodies in E canis-endemic regions is associated with higher incidence of CKD in dogs.

A retrospective evaluation of the relationship between symmetric dimethylarginine, creatinine and body weight in hyperthyroid cats.

Hyperthyroidism in cats can mask changes in renal function, including chronic kidney disease (CKD), because of hyperfiltration and muscle loss. Symmetric dimethylarginine (SDMA) has been shown to increase earlier than creatinine in cats with renal dysfunction, and, unlike creatinine, SDMA is not impacted by lean muscle mass. The aim of this study was to describe the relationship between SDMA, creatinine, body weight and TT4 over time during treatment of hyperthyroidism. Cats were retrospectively identified from the US IDEXX Reference Laboratories database where TT4, SDMA and creatinine were measured on the same cat at multiple time points. A hyperthyroid treated group was identified (TT4 ≤ 4.7 µg/dL and decreased by a minimum of 2.5 µg/dL) that had body weight and laboratory results available from more than one visit, and was used to evaluate body weight, creatinine, SDMA and TT4 pre-treatment and at 1-30, 31-60, 61-90, 91-120 days post-treatment. Creatinine significantly decreased with increasing concentrations of TT4 (Spearman's ρ = -0.37, P < 0.001), whereas SDMA did not. Body weight, SDMA and creatinine concentrations significantly increased during the immediate 1-30 day post-treatment period (P < 0.012, P < 0.001, P < 0.001, respectively). During treatment creatinine continued to increase as cats gained weight. In contrast, SDMA remained stable during treatment and was comparable to age-matched control cats. Therefore, SDMA may be a more reliable biomarker of renal function than creatinine in hyperthyroid cats before and during treatment.

Coproantigen Detection Augments Diagnosis of Common Nematode Infections in Dogs.

Microscopic methods which employ active or passive flotation have been used to detect parasite diagnostic stages in the feces of companion animals for many years. More recently, coproantigen ELISAs for the detection of excretory/secretory products from intestinal nematodes have been introduced. These assays can identify the presence of parasites when eggs are not recovered by flotation (e.g. prepatent infection or intermittent egg shedding). The study was designed to assess the added benefit of these coproantigen tests in canine fecal diagnostics. The work was performed at 3 separate sites where canine fecal samples were each independently evaluated by both centrifugal flotation with an expert examiner (CFE) and passive flotation with a less experienced examiner. All samples were also tested using coproantigen ELISA to detect ascarid, hookworm, or whipworm antigen (IDEXX Laboratories, Inc, Westbrook, Maine). A total of 1202 samples were collected; 626 were from shelter dogs and 576 were from pet dogs. CFE recovered ascarid eggs in 58 samples, hookworm eggs in 229 samples, and whipworm eggs in 95 samples. Of the positive samples identified by CFE, the PFE and ELISA identified 40 and 51 ascarid samples, 188 and 203 hookworm samples, and 65 and 67 whipworm positive samples, respectively. The coproantigen ELISA identified 8 ascarid, 82 hookworm, and 22 whipworm positive samples that were not detected by CFE. The combined results of passive flotation and the coproantigen ELISA improved the percent agreement with centrifugal flotation, suggesting that greater sensitivity of detection may be achieved through the use of complementary diagnostic methods. However, errors of misidentification and poor recovery apparently introduced by less experienced examiners using an inferior flotation method remained. A diagnostic approach that combines coproantigen assays with centrifugal flotation and examination by an expert allows detection of more ascarid, hookworm, and whipworm infections.

Comparative performance of IDEXX SDMA Test and the DLD SDMA ELISA for the measurement of SDMA in canine and feline serum.

Kidney disease is common in companion animals, and traditionally diagnosed with serum creatinine concentration (sCr), blood urea nitrogen, and abnormal urinalysis findings. Symmetric dimethylarginine (SDMA) is a novel kidney biomarker that reflects glomerular filtration rate, increasing earlier than sCr with acute kidney injury and chronic kidney disease. This prospective study compared accuracy and precision of two commercial SDMA assays, the IDEXX SDMA Test and the DLD SDMA ELISA, relative to the established reference method, liquid chromatography/mass spectrometry (LC-MS). Thirty canine and 30 feline pooled serum samples were used to evaluate accuracy compared to LC-MS. Pooled canine samples with a low SDMA concentration and pooled feline samples with a high SDMA concentration were used to evaluate precision. Using a best fit linear model, the IDEXX SDMA Test resulted in a slope of 1.06 and an intercept of 0.34, with R2 = 0.99, and the DLD SDMA ELISA resulted in a slope of 0.37 and an intercept of 11.33, with R2 = 0.27, when compared to LC-MS. Estimated bias over a clinically relevant range for SDMA (10-45 µg/dL) was 1-2 µg/dL for the IDEXX SDMA Test, while DLD SDMA ELISA showed considerable bias, 5-8 µg/dL. Day-to-day precision analysis of the low SDMA concentration samples showed 7.7% total coefficient of variation (CV) for the IDEXX SDMA Test and 31.1% for the DLD SDMA ELISA. For the high SDMA concentration samples, total CV was 2.3% for the IDEXX SDMA Test and 28.2% for the DLD SDMA ELISA. In this study the IDEXX SDMA Test was more accurate and more precise in macroscopically normal serum than the DLD SDMA ELISA when compared to the reference method of LC-MS. The IDEXX SDMA Test is more suitable for clinical use in the diagnosis and monitoring of kidney disease in dogs and cats.

RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development.

Ligation of erythropoietin (EPO) receptor (EPOR) JAK2 kinase complexes propagates signals within erythroid progenitor cells (EPCs) that are essential for red blood cell production. To reveal hypothesized novel EPOR/JAK2 targets, a phosphotyrosine (PY) phosphoproteomics approach was applied. Beyond known signal transduction factors, 32 new targets of EPO-modulated tyrosine phosphorylation were defined. Molecular adaptors comprised one major set including growth factor receptor-bound protein 2 (GRB2)-associated binding proteins 1-3 (GAB1-3), insulin receptor substrate 2 (IRS2), docking protein 1 (DOK1), Src homology 2 domain containing transforming protein 1 (SHC1), and sprouty homologue 1 (SPRY1) as validating targets, and SPRY2, SH2 domain containing 2A (SH2D2A), and signal transducing adaptor molecule 2 (STAM2) as novel candidate adaptors together with an ORF factor designated as regulator of human erythroid cell expansion (RHEX). RHEX is well conserved in Homo sapiens and primates but absent from mouse, rat, and lower vertebrate genomes. Among tissues and lineages, RHEX was elevated in EPCs, occurred as a plasma membrane protein, was rapidly PY-phosphorylated >20-fold upon EPO exposure, and coimmunoprecipitated with the EPOR. In UT7epo cells, knockdown of RHEX inhibited EPO-dependent growth. This was associated with extracellular signal-regulated kinase 1,2 (ERK1,2) modulation, and RHEX coupling to GRB2. In primary human EPCs, shRNA knockdown studies confirmed RHEX regulation of erythroid progenitor expansion and further revealed roles in promoting the formation of hemoglobinizing erythroblasts. RHEX therefore comprises a new EPO/EPOR target and regulator of human erythroid cell expansion that additionally acts to support late-stage erythroblast development.

Differential expression of NADPH oxidases in megakaryocytes and their role in polyploidy.

Megakaryocytes (MKs) undergo an endomitotic cell cycle, leading to polyploidy. We examined the expression of the flavoproteins and oxidative stress-promoting enzymes, NADPH oxidases (Nox's), in MKs because of their known role in promoting the cell cycle. Although the expression of Nox isoforms varies between cell types, they are induced at the mRNA level by mitogenic stimuli. Western blotting or reverse transcription-polymerase chain reaction of purified mouse MKs isolated from thrombopoietin (TPO)-treated bone marrow (BM) cultures indicated high expression of Nox1, a weak expression of Nox4, and no significant expression of Nox2. Immunofluorescence of freshly isolated MKs confirmed strong expression of Nox1 in one-third of MKs, whereas Nox1 staining was detected in nearly all MKs in TPO-stimulated BM cultures. Treatment of mouse BM cultures with Nox inhibitors resulted in accumulation of MKs with low DNA content levels and significant reduction of higher ploidy MKs. Purified, Nox-inhibited MKs showed a notable decrease in the level of the G(1) phase cyclin E, a cyclin associated with MK polyploidy, and its up-regulation restored most of the effect of Nox inhibitors. Hence, this study shows the expression of Nox isoforms in MKs and highlights a potential role of flavoproteins in promoting polyploidization in this lineage.

Upregulation of Nox4 in the aging vasculature and its association with smooth muscle cell polyploidy.

Our recent reports indicated that polyploidization of aortic vascular smooth muscle cells (VSMC) serves as a biomarker for aging, and that the polyploid state is linked to a higher incidence of senescence in vivo. Here, we found that NADPH oxidase 4 (Nox4) expression is augmented in VSMC from aortas of old rats and that Nox4 levels are increased in polyploid VSMC in comparison to diploid cells in vivo. Seeking to determine if Nox4 upregulation plays a causal role in the accumulation of polyploid cells, we performed ploidy analysis on primary VSMC transduced with Nox4 adenovirus. We observed a consistent accumulation of polyploid cells and a concomitant decrease in the percentage of diploid cells in Nox4 overexpressing cells in comparison to controls or to cells overexpressing dominant negative Nox4. Further exploration of this phenomenon in VSMC cultures identified a Nox4-induced decrease in the chromosome passenger protein, survivin, whose absence and mislocalization during polyploidization was previously shown to induce VSMC polyploidy. Taken together, our study is the first to show increased Nox4 levels in VSMC during aging, and to demonstrate its role in induction of polyploidy in this lineage.

Direct visualization of the endomitotic cell cycle in living megakaryocytes: differential patterns in low and high ploidy cells.

Endomitosis in megakaryocytes (MKs) involves repeated DNA replication in the absence of cytokinesis and is a crucial part of MK development. However, chromosomal dynamics have never been observed in living MKs. We developed a new transgenic mouse model in which the expression of human histone H2B fused in-frame to green fluorescent protein is targeted to MKs. Ex vivo time-lapse microscopy analysis indicated that chromosomal condensation occurs at early mitosis in all MKs. In high ploidy MKs (>or=8N), late anaphase was marked by a ring-type alignment of chromosomes with multiple territories formed between them. By contrast, in low ploidy MKs mitotic chromosomes segregated to form two groups separated by a clear space before re-joining to one cluster. This is the first study to document chromosomal segregation patterns during endomitosis ex vivo and to indicate their potential differential regulation in low and high ploidy cells.

Survivin overexpression alone does not alter megakaryocyte ploidy nor interfere with erythroid/megakaryocytic lineage development in transgenic mice.

The level of survivin was reported to be scarce in mouse megakaryocytes (MKs) compared with erythroid cells. Considering this finding and previously reported in vitro data showing decreased MK ploidy upon retroviral-mediated overexpression of survivin, we sought to examine whether ectopic survivin expression in the MK lineage might alter ploidy level in vivo. Here we report the generation of 2 tissue specific hematopoietic transgenic mouse models, one expressing survivin in both the erythroid and MK lineages and the other expressing survivin solely in the MK lineage. Survivin protein overexpression was confirmed in MKs and erythrocytes. Surprisingly, analysis of both transgenic mouse lines showed no detectable changes in MK number, ploidy level, and platelet and erythrocyte counts, as compared with control mice. We conclude that elevated survivin expression does not alter MK/erythroid lineage development and that elevated survivin, alone, does not interfere with MK ploidy in vivo.

The A2b adenosine receptor protects against vascular injury.

The A2b adenosine receptor (A2bAR) is highly abundant in bone marrow macrophages and vascular smooth muscle cells (VSMC). To examine the functional significance of this receptor expression, we applied a femoral artery injury model to A2bAR knockout (KO) mice and showed that the A2bAR prevents vascular lesion formation in an injury model that resembles human restenosis after angioplasty. While considering related mechanisms, we noted higher levels of TNF-alpha, an up-regulator of CXCR4, and of VSMC proliferation in the injured KO mice. In accordance, CXCR4, which is known to attract progenitor cells during tissue regeneration, is up-regulated in lesions of the KO mice. In addition, aortic smooth muscle cells derived from A2bAR KO mice display greater proliferation in comparison with controls. Bone marrow transplantation experiments indicated that the majority of the signal for lesion formation in the null mice originates from bone marrow cells. Thus, this study highlights the significance of the A2bAR in regulating CXCR4 expression in vivo and in protecting against vascular lesion formation.

Vascular smooth muscle cell polyploidy: an adaptive or maladaptive response?

Polyploidy is a state in which a cell contains multiple copies of its entire genome, while a normal diploid cell contains only two sets of homologous chromosomes. Although widely studied and pervasive in nature, the signals and mechanisms of polyploidization and its accompanying operational consequences are still unclear. This review focuses on relevant questions in deciphering the regulation of polyploidization of vascular smooth muscle cells (VSMC) in mammals and the role of polyploidy in various vascular pathologies, such as hypertension and aging. Additionally, we will explore new investigations in polyploidization of VSMCs involving the rapidly expanding fields of oxidative stress and senescence. J. Cell. Physiol. 215: 588-592, 2008. (c) 2008 Wiley-Liss, Inc.