Wenduo Gu

All Publications

• Preclinical evaluation of high-resolution CT, 18F-FDG, and 18F-NaF PET imaging for longitudinal monitoring of atherosclerosis. European journal of nuclear medicine and molecular imaging Tamboline, M., Collins, J., Jackson, W., Gu, W., Worssam, M., Cheng, P., David, J., Taschereau, R., Chatziioannou, A. F., Jackson, S., Xu, S., Ikotun, O. F. 2025

  Abstract

  Detection of atherosclerosis is essential to the management and prevention of life-threatening cardiovascular events. Although non-invasive imaging modalities, such as 18F-sodium fluoride (18F-NaF), 18F-fluorodeoxyglucose (18F-FDG) PET, and CT, visualize distinct hallmarks of atherosclerosis, there has yet to be a singular multi-cohort interrogation of their strengths and limitations. Thus, we focused on identifying the optimal approach for visualizing atherosclerosis at different stages of disease progression.In this study, 6-week-old, male, ApoE deficient mice (Apoe-/-) were placed on a high cholesterol diet for 12-20 weeks to induce calcific atherosclerotic disease. Age-matched, male, wildtype (WT) C57BL/6 mice fed with regular chow served as the control group. Mice were imaged at 12, 15, 18, and 20 weeks after starting their respective diets. To follow the progression of calcified atherosclerotic lesions, at each time point, in vivo, 18F-NaF microPET/CT images were acquired 1 h and 3 h post tracer i.v. injection. In a separate cohort, in vivo 18F-FDG PET/CT images were acquired at 3 and 5 h post tracer i.v. injection to follow inflammation as a result of progressive atherosclerotic lesion formation. High-resolution microCT images were acquired for all mice to visualize aorta calcification. After each imaging session, a subset (n = 3) was euthanized from each group and histological analysis of the aorta was performed to confirm disease progression.In this comparative study, within the same cohort, 18F-NaF PET detected atherosclerotic calcification earlier than microCT. At both 1 and 3 h post-injection (p.i.), calcified lesions were clearly detected by 18F-NaF with a six-fold higher signal in Apoe-/- compared to WT mice. Interestingly, 18F-NaF signal peaked at week 18, whereas aortic CT signal progressively increased with a 13-, 16-, and 29-fold at 15, 18, and 20 weeks, respectively. 18F-FDG arortic accumulation at weeks 12 and 15, were significantly greater in Apoe -/- mice than WT control when images were acquired at 5 h but not at 3 h p.i.. In contrast to histological analysis, at ≥ 16 weeks where inflammation is significantly elevated, 18F-FDG was equivalent in Apoe-/- and WT control mice and significantly reduced with disease progression.Our results show that 18F-NaF PET and 18F-FDG PET are sensitive imaging modalities for the early detection of atherosclerotic lesions. However, both 18F-NaF PET and high-resolution microCT prove to be effective methods for monitoring late-stage and progressive disease.

  View details for DOI 10.1007/s00259-025-07276-1

  View details for PubMedID 40289041

  View details for PubMedCentralID 8274865

• Chemokine (C-C Motif) Ligand 2 Expressing Adventitial Fibroblast Expansion During Loeys-Dietz Syndrome Aortic Aneurysm Formation. Arteriosclerosis, thrombosis, and vascular biology Dalal, A. R., Pedroza, A. J., Kim, J., Gilles, C., Gu, W., Kusadokoro, S., Shad, R., Mitchel, O., Jackson, W., Hiesinger, W., Berry, G., Gallo MacFarlane, E., Quertermous, T., Cheng, P., Fischbein, M. P. 2025

  Abstract

  Loeys-Dietz syndrome (LDS), caused by mutations in the TGF-β (transforming growth factor-β) signaling cascade, leads to aggressive thoracic aneurysms. While vascular smooth muscle cell (SMC) phenotype modulation has been implicated in thoracic aneurysm formation, we sought to characterize the role of cell state transitions in LDS aneurysm pathogenesis.We performed single-cell transcriptomic characterization of aortic root/ascending aorta from a murine LDS model (Tgfbr2G357W/+ versus littermate WT [wild-type] control) at 8 weeks, 24 weeks, and aortic root/ascending aortic samples from human LDS surgical specimens (n=5 LDS [TGFBR1/2] and n=2 donor control) to understand cell state transitions and transcriptomic alterations in LDS. Select cell markers were spatially localized with RNA in situ hybridization, immunofluorescence, and immunohistochemistry. Single-cell RNA sequencing of murine and human LDS samples (>30 000 cells) revealed unique SMC, fibroblast, and macrophage transcriptomic profiles in LDS.Instead of SMC phenotypic modulation seen in Marfan syndrome, transcriptomic alterations observed in LDS are most prominent in the adventitial fibroblast in the Tgfbr2G357W/+ mouse model. While a distinct modulated SMC cluster does not appear in Tgfbr2G357W/+, SMCs transcriptomically differ from WT counterparts. Adventitial fibroblasts were activated into a proinflammatory state associated with increased macrophage recruitment (Ccl2, Il6, Ccl7, and Cxcl2) and fibrotic response genes (Col1a1, Col1a2, and Col3a1), with a 6-fold increase in aortic wall macrophage content in Tgfbr2G357W/+ compared with WT. Similar findings were also observed in human LDS aortic samples with increased proinflammatory adventitial fibroblast transcriptomic program in parallel with heightened macrophage recruitment.Despite phenotypic similarities in aneurysm formation, the dominant cellular and molecular mechanism of Marfan syndrome and LDS aneurysms are distinct. LDS mouse and human adventitial fibroblasts transcriptomically modulate into a proinflammatory state. Adventitial fibroblasts, in addition to SMCs, are another important pathological cell population during LDS aneurysm formation to consider for targeted therapy to potentially impede LDS aneurysm formation.

  View details for DOI 10.1161/ATVBAHA.124.322069

  View details for PubMedID 40109260

• Residual popliteal vein thrombosis after endovascular treatment of mixed-type lower extremity deep vein thrombosis is relevant to post-thrombotic syndrome. Journal of vascular surgery. Venous and lymphatic disorders Qiu, J., Ai, W., Gu, W., Lin, S., Xiao, J., Huang, Y., Qiu, T., Xu, B., Zhang, Z. 2024: 102002

  Abstract

  Patients with mixed-type lower extremity deep vein thrombosis (LEDVT) have a higher incidence of post-thrombotic syndrome (PTS) following endovascular treatment (EVT). This study aimed to identify risk factors associated with PTS in these patients post-EVT.This retrospective study included patients diagnosed with acute mixed-type LEDVT who underwent EVT between January 2020 and December 2022. Patient assessments were conducted using ultrasound and the Villalta scale. Baseline characteristics, management details, and follow-up findings were compared between patients who developed PTS and those who did not at six months after EVT. Cox regression and nomogram analyses were performed to identify risk factors associated with the development of PTS.The study enrolled 118 patients, of which 103 completed the follow-up. Among them, 24.3% developed post-thrombotic syndrome (PTS) within six months. Significant differences between the PTS and non-PTS groups were found concerning residual thrombosis in the popliteal, common femoral, and femoral veins. Multivariate Cox regression analysis indicated that residual popliteal vein thrombosis (RPVT) (HR 4.93, 95% CI 1.61-15.11) and preoperative iliac vein stenosis (HR 3.21, 95% CI 1.11-9.33) were significant risk factors for PTS. Additionally, subgroup analysis for preoperative iliac vein stenosis and sensitivity analysis confirmed that RPVT remained a risk factor for PTS (HR 4.48, 95% CI 1.27-15.84).Our study demonstrated a positive association between residual popliteal vein thrombosis (RPVT) and PTS in patients with extensive mixed-type LEDVT after EVT. These findings suggest that intensive monitoring and aggressive therapeutic interventions may be required for patients with RPVT to reduce the risk of PTS.

  View details for DOI 10.1016/j.jvsv.2024.102002

  View details for PubMedID 39521056

• Genetic and functional analysis of Raynaud's syndrome implicates loci in vasculature and immunity. Cell genomics Tervi, A., Ramste, M., Abner, E., Cheng, P., Lane, J. M., Maher, M., Valliere, J., Lammi, V., Strausz, S., Riikonen, J., Nguyen, T., Martyn, G. E., Sheth, M. U., Xia, F., Docampo, M. L., Gu, W., Esko, T., Saxena, R., Pirinen, M., Palotie, A., Ripatti, S., Sinnott-Armstrong, N., Daly, M., Engreitz, J. M., Rabinovitch, M., Heckman, C. A., Quertermous, T., Jones, S. E., Ollila, H. M. 2024: 100630

  Abstract

  Raynaud's syndrome is a dysautonomia where exposure to cold causes vasoconstriction and hypoxia, particularly in the extremities. We performed meta-analysis in four cohorts and discovered eight loci (ADRA2A, IRX1, NOS3, ACVR2A, TMEM51, PCDH10-DT, HLA, and RAB6C) where ADRA2A, ACVR2A, NOS3, TMEM51, and IRX1 co-localized with expression quantitative trait loci (eQTLs), particularly in distal arteries. CRISPR gene editing further showed that ADRA2A and NOS3 loci modified gene expression and in situ RNAscope clarified the specificity of ADRA2A in small vessels and IRX1 around small capillaries in the skin. A functional contraction assay in the cold showed lower contraction in ADRA2A-deficient and higher contraction in ADRA2A-overexpressing smooth muscle cells. Overall, our study highlights the power of genome-wide association testing with functional follow-up as a method to understand complex diseases. The results indicate temperature-dependent adrenergic signaling through ADRA2A, effects at the microvasculature by IRX1, endothelial signaling by NOS3, and immune mechanisms by the HLA locus in Raynaud's syndrome.

  View details for DOI 10.1016/j.xgen.2024.100630

  View details for PubMedID 39142284

• Genome-Wide Genetic Associations Prioritize Evaluation of Causal Mechanisms of Atherosclerotic Disease Risk. Arteriosclerosis, thrombosis, and vascular biology Quertermous, T., Li, D. Y., Weldy, C. S., Ramste, M., Sharma, D., Monteiro, J. P., Gu, W., Worssam, M. D., Palmisano, B. T., Park, C. Y., Cheng, P. 2024; 44 (2): 323-327

  Abstract

  The goal of this review is to discuss the implementation of genome-wide association studies to identify causal mechanisms of vascular disease risk.The history of genome-wide association studies is described, the use of imputation and the creation of consortia to conduct meta-analyses with sufficient power to arrive at consistent associated loci for vascular disease. Genomic methods are described that allow the identification of causal variants and causal genes and how they impact the disease process. The power of single-cell analyses to promote genome-wide association studies of causal gene function is described.Genome-wide association studies represent a paradigm shift in the study of cardiovascular disease, providing identification of genes, cellular phenotypes, and disease pathways that empower the future of targeted drug development.

  View details for DOI 10.1161/ATVBAHA.123.319480

  View details for PubMedID 38266112