About

Douglas Alan Marchuk is the James B. Duke Distinguished Professor of Molecular Genetics and Microbiology at Duke University. He also serves as Professor of Molecular Genetics and Microbiology, Professor of Cell Biology, Director of the Duke University Program in Genetics and Genomics, Director of the Center for Experimental Genetics, and is a member of the Duke Cancer Institute. His laboratory focuses on the genetics of cardiovascular disease, utilizing both human and mouse models to study inherited diseases of vascular dysplasia. The research aims to understand the role of genes and gene products in vascular morphogenesis and the pathology of related disorders by identifying genetic loci responsible for these diseases and investigating the molecular and cellular functions of the mutant proteins involved. The lab employs biochemical, cell biological, and in vivo mouse models, including knockout and transgenic mice, to study disease mechanisms and potential therapeutic approaches. A significant portion of his work has been dedicated to Cerebral Cavernous Malformations (CCM), a congenital vascular anomaly of the brain. His lab identified two of the three known genes causing CCM and provided evidence supporting the "two-hit" mutation model for lesion formation. Mouse models for CCM genes have been developed to study lesion development and test novel therapies. Additionally, Marchuk's lab investigates Sturge-Weber Syndrome (SWS), a rare congenital vascular disorder characterized by facial port-wine birthmarks and neurological symptoms. His team identified a somatic mutation in the GNAQ gene as the cause of SWS and port-wine stains, confirming a long-standing hypothesis about somatic mosaicism in this disease. Beyond vascular dysplasia, Marchuk's research includes using mouse forward genetics to identify modifier genes that influence disease severity and progression in models of heart disease and ischemic stroke. For example, in a mouse model of cardiomyopathy, his lab identified several heart failure modifier loci and is exploring the human orthologs and potential therapeutic targets. Similarly, his work on ischemic stroke modifier genes aims to uncover genetic factors that affect tissue damage after stroke, with the goal of identifying new targets for intervention. Overall, Marchuk's research integrates genetic, molecular, and animal model approaches to elucidate the mechanisms underlying vascular diseases and to develop novel therapeutic strategies.

Research topics

• Biology
• Medicine
• Genetics
• Bioinformatics
• Neuroscience
• Pathology
• Cell biology
• Cardiology
• Internal medicine
• Cancer research

Selected publications

• Abstract DP225: Inflammation and Angiogenic Biomarkers Associated With Familial Cerebral Cavernous Malformation, Hereditary Hemorrhagic Telangiectasia and Sturge-Weber Syndrome

  Stroke · 2026-01-29

  article

  Introduction: Circulating plasma protein biomarkers may distinguish between related diseases that share common disease mechanisms, such as neuroinflammation and angiogenesis. We aimed to compare inflammatory and angiogenic protein levels between three rare vascular diseases that all have a brain vascular malformation phenotype: familial Cerebral Cavernous Malformation (FCCM), Hereditary Hemorrhagic Telangiectasia (HHT), and Sturge-Weber Syndrome (SWS). Methods: We measured plasma levels of 22 proteins related to inflammation and angiogenesis in 428 individuals enrolled in the Brain Vascular Malformation Consortium (BVMC), including 472 blood samples (216 FCCM, 206 HHT and 50 SWS), using the Angiome multiplex ELISA biomarker panel. Protein levels were assayed in two batches, measured in duplicate, log-transformed and averaged for analysis. We compared biomarker levels between diseases using multivariable linear regression, adjusting for age at blood collection, sex, and assay batch ; cluster-robust standard errors accounted for within-person correlation and Bonferroni-correction for multiple testing. Exponentiated coefficients are reported as Proportional Increase (PI) for protein levels between groups. Results: All 22 proteins were successfully measured in the 472 samples: 216 FCCM (42% male, median age 47 years), 206 HHT (48% male, median age 42 years), and 50 SWS (46% male, median age 18 years). As expected, HHT cases with endoglin mutations had ~50% lower endoglin levels. In CCM compared to HHT, we observed higher levels of endoglin (PI=1.45, P<0.001), GP130 (PI=1.26, P<0.001) and IL10 (PI=1.31, P=0.048), and lower levels of IL6R (PI=0.85, P<0.001) and IL1B (PI=0.38, P<0.001). In CCM compared to SWS cases, we observed a higher level of TIE2 (PI=1.31, P=0.002) and lower levels of IL6R (PI=0.80, P<0.001) and IL6 (PI=0.57, P=0.035). In HHT compared to SWS, we observed a higher level of VEGFR1 (PI=1.50, P=0.032) and lower levels of endoglin (PI=0.67, P<0.001) and IL6 (PI=0.55, P=0.039). Conclusions: We identified several circulating plasma biomarkers with a role in inflammation and angiogenesis that differ between FCCM, HHT and SWS cohorts, including endoglin, GP130, IL1B, IL10, IL6, IL6R, TIE2, and VEGFR1. These proteins may play a role in specific underlying disease mechanisms.

  PublisherDOI

• Somatic PIK3CA Activating Mutation in a Plexiform Lesion of a Patient With HHT and PAH

  JACC Case Reports · 2026-01-21

  articleOpen access

  BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) and pulmonary arterial hypertension (PAH) are rare vascular diseases whose pathobiology is poorly understood. HHT is characterized by arteriovenous malformations, whereas PAH by an occlusive pulmonary vasculopathy that includes plexiform lesions. CASE SUMMARY: A female patient with PAH and HHT developed right heart failure with severe hypoxemia despite years of medical treatment for PAH, necessitating a heart-lung transplantation. DISCUSSION: Histological and molecular analysis of the lung explant revealed that, in addition to the inherited HHT-causing variant in the endoglin gene, a plexiform lesion harbored an oncogenic, somatic phosphoinositide-3-kinase, PIK3CA activating mutation, which in this case may have driven endothelial cell proliferation. TAKE-HOME MESSAGES: This novel discovery sheds light on the molecular basis of plexiform lesion development in this rare case of combined PAH and HHT, highlighting a potential role of somatic mutations in driving endothelial cell proliferation in plexiform lesions.

  PublisherDOI

• TIE2 links MEKK3–KLF2/4 and PI3K signaling in cerebral cavernous malformation

  The Journal of Experimental Medicine · 2026-03-27

  article

  Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system that can cause strokes and seizures. Aggressive CCM growth follows an endothelial cell two-hit mechanism in which enhanced MEKK3-KLF2/4 signaling stimulates PI3K signaling, but how these pathways are linked has been undefined. Here, we use human CCM specimens, two mouse models of CCM disease, and primary human endothelial cells to examine the roles of the major endothelial growth factor receptors, VEGFR2 and TIE2. We find no evidence of augmented VEGFR2 signaling in CCM lesions, and neither genetic nor pharmacologic blockade of VEGFR2 reduced CCM formation in mouse models. Instead, we observe markedly increased phospho-TIE2 levels in human and mouse CCM lesions, MEKK3-KLF2/4-driven induction of TIE2 receptor expression, and almost complete rescue of CCM formation following genetic or pharmacologic TIE2 blockade in mouse models. Our studies identify TIE2 as the molecular link between the MEKK3-KLF2/4 and PI3K signaling pathways during CCM formation and suggest that targeting TIE2 may be an effective means to treat human CCM disease.

  PublisherDOI

• Figure S3 from Somatic Uniparental Disomy of <i>PTEN</i> in Endothelial Cells Causes Vascular Malformations in Patients with PTEN Hamartoma Tumor Syndrome

  2025-07-03

  preprintOpen access

  <p>PTEN loss in ECs causes lymphatic vascular malformations in the ear skin of mice.</p>

  PublisherOA PDFDOI

• Somatic Uniparental Disomy of <i>PTEN</i> in Endothelial Cells Causes Vascular Malformations in Patients with PTEN Hamartoma Tumor Syndrome

  Cancer Discovery · 2025-03-28 · 8 citations

  articleOpen access

  PTEN hamartoma tumor syndrome (PHTS) is a rare tumor risk disorder caused by germline loss-of-function mutations in PTEN. Half of these patients develop vascular malformations, a hamartoma characterized by overgrowth of vessels. In this study, we harness biopsies and patient-derived endothelial cells (EC) to study the genetic etiology of PHTS-related vascular malformations. We discover that these lesions are generated by somatic loss of the PTEN wild-type allele through copy-neutral loss of heterozygosity, leading to somatic uniparental disomy of the PTEN-mutated allele in ECs. We established a mouse model of PHTS-related vascular malformations and identified that the mTOR inhibitor rapamycin and AKT inhibitor capivasertib block vascular lesion growth. As proof-of-concept for clinical activity, off-label treatment with rapamycin of two patients with PHTS reduced vascular overgrowth and abrogated lesion-associated pain. Overall, our results uncover the genetic cause of vascular malformations in patients with PHTS and open new avenues for therapeutic intervention. SIGNIFICANCE: Somatic loss of PTEN in ECs causes vascular malformations in patients with the tumor risk syndrome PHTS. These lesions respond to PI3K signaling inhibition. See related commentary by Del Prior and Toker, p. 1306.

  PublisherOA PDFDOI

• Table S2 from Somatic Uniparental Disomy of &lt;i&gt;PTEN&lt;/i&gt; in Endothelial Cells Causes Vascular Malformations in Patients with PTEN Hamartoma Tumor Syndrome

  2025-07-03

  preprintOpen access

  &lt;p&gt;List of primers.&lt;/p&gt;

  PublisherOA PDFDOI

• Abstract WMP99: Circulating Plasma Biomarkers Associated with Familial Cerebral Cavernous Malformation, Hereditary Hemorrhagic Telangiectasia and Sturge-Weber Syndrome

  Stroke · 2025-01-30

  article

  Introduction: Circulating plasma protein profiling in individuals with brain vascular disorders may aid in the identification of robust diagnostic biomarkers, stratification of high-risk patients for treatment, and monitoring of disease progression or treatment response. This Brain Vascular Malformation Consortium (BVMC) study aimed to identify circulating inflammatory and angiogenic proteins that associate with familial Cerebral Cavernous Malformation (FCCM), Hereditary Hemorrhagic Telangiectasia (HHT), or Sturge-Weber Syndrome (SWS). Methods: We used the Angiome multiplex ELISA biomarker panel to assess the circulating plasma levels of 22 proteins related to inflammation and angiogenesis in 234 individuals enrolled in the BVMC, including 114 FCCM, 101 HHT and 19 SWS cases. Protein levels were measured in duplicate and absolute measurements obtained. We tested for biomarker associations between disease states using linear regression models adjusting for age at blood collection and sex. We calculated the intraclass correlation coefficient (ICC) to describe the similarity in replicates, and report proportional increase (PI) for protein levels for statistically significant results with Bonferroni-corrected P-values &lt;0.05 (adjusted for 22 markers). Results: All 22 proteins were successfully measured in the 114 FCCM (39% male, median age 52 years), 101 HHT (49% male, median age 42 years, 36% with brain arteriovenous malformation), and 19 SWS (53% male, median age 15 years). The ICC was high for all markers (range 0.904-0.990). As expected, HHT cases with endoglin mutations had ~50% lower endoglin. We observed increased levels of endoglin (PI=1.38, 95% CI:1.27-1.50, P=6.50E-13) and IL10 (PI=1.48, 95% CI:1.16-1.91, P=0.04) in CCM compared to HHT cases, and decreased IL8 (PI=0.60, 95% CI:0.43-0.83, P=0.04) and OPN (PI=0.63, 95% CI:0.47-0.84, P=0.04) in CCM compared to SWS cases. We also observed higher levels of endoglin (PI=1.45, 95% CI:1.24-1.71, P=1.47E-04), GP130 (PI=1.24, 95% CI:1.11-1.38, P=2.91E-03), and OPN (PI=1.80, 95% CI:1.36-2.40, P=1.13E-03), and lower levels of IL1β (PI=0.30, 95% CI:0.15-0.59, P=0.01) in SWS compared to HHT cases. Conclusions: We identified circulating plasma biomarkers associated with FCCM, HHT and SWS. Larger ongoing work will confirm whether these inflammatory/angiogenic markers are relevant as potential diagnostic or therapeutic targets or have broader implications as clinical biomarkers in other brain vascular diseases.

  PublisherDOI

• The Role of Somatic Mutation in Hereditary Hemorrhagic Telangiectasia Pathogenesis

  Journal of Clinical Medicine · 2025-06-24 · 4 citations

  reviewOpen accessSenior authorCorresponding

  were discovered in individuals with HHT, haploinsufficiency, a 50% reduction in the encoded protein, was proposed as the molecular mechanism of HHT. However, the focal and discrete nature of HHT-associated vascular malformations suggested to others that vascular malformation genesis requires an additional, local trigger. In this review, we discuss the evidence for the Knudsonian two-hit mutation mechanism of vascular malformation pathogenesis in HHT, where the inherited, heterozygous mutation is augmented by an acquired somatic mutation in the remaining normal copy of the gene. We consider the mechanisms of HHT-vascular malformation development in the broader context of the emerging role of somatic mutations in both sporadic and inherited vascular malformations. We discuss different mechanisms of biallelic gene inactivation in HHT, difficulties with the detection of all possible mechanisms of biallelic inactivation, and issues related to the somatic mosaic nature of the lesion. We then discuss the critical importance of non-genetic factors on the pathogenesis of HHT-associated vascular malformations. Finally, we discuss the implications of the two-hit mutation mechanism for the design of novel treatments for HHT.

  PublisherOA PDFDOI

• Figure S2 from Somatic Uniparental Disomy of &lt;i&gt;PTEN&lt;/i&gt; in Endothelial Cells Causes Vascular Malformations in Patients with PTEN Hamartoma Tumor Syndrome

  2025-07-03

  preprintOpen access

  &lt;p&gt;Loss of endothelial PTEN protein expression in vascular malformations of patients with PHTS.&lt;/p&gt;

  PublisherOA PDFDOI

• Recurrent somatic copy number alterations in resected cerebral cavernous malformations

  Human Genomics · 2025-12-09

  articleOpen accessSenior author

  Cerebral Cavernous Malformations (CCMs) are brain vascular lesions that occur in sporadic or inherited (autosomal dominant) forms. The malformations are driven by mutations in KRIT1, CCM2, PDCD10 or MAP3K3. Known oncogenic variants in PIK3CA accompany CCM-specific variants in lesions. While the primary genetic etiology of CCM lesions is relatively well understood, a subset of lesions does not yet have an identified molecular genetic etiology. Moreover, whether large genomic alterations occur somatically in CCM lesion tissue has been largely unexplored. In PIK3CA + cancers, large somatic copy number alterations ('CNAs') are frequent, with whole genome doubling and aneuploidy identified in most tumors. Such CNA events are known to be associated with course of disease and therapeutic response. In this study, using whole genome SNP-genotyping and Mosaic Chromosome Alteration (MoChA) analysis, we identify the presence of large (> 1 MB) somatic CNAs in CCMs, with specific enrichment of events in chromosome arms 16p,19p,17q, 20q. We also identify additional chromosome arm level events encompassing known CCM genes in a subset of lesions. Thus, we characterize a pattern of large genomic events that had remained hidden by the insensitivity of the molecular and analytical methods previously used. Finally, we propose that similar events may be found in other vascular malformations or PIK3CA overgrowth syndromes that have yet to be analyzed in this manner.

  PublisherDOI

Recent grants

• Signaling Aberrations and Cerebral Cavernous Malformation Pathogenesis

  NIH · $25.9M · 2015–2025

• NIH Grant R21NS091589

  NIH · $437k · 2018

• Brain Vascular Malformation Consortium: Predictor's of Clinical Course

  NIH · $39.3M · 2009–2026

• Novel Targets for Stroke Intervention - Gene Discovery for Modulators of Infarction

  NIH · $3.2M · 2017–2023

• NIH Grant R01HL049171

  NIH · $2.9M · 2006

Frequent coauthors

• William L. Young

  Rutgers Sexual and Reproductive Health and Rights

  197 shared

• Michael T. Lawton

  St. Joseph's Hospital and Medical Center

  142 shared

• Carol Gallione

  Duke University Hospital

  134 shared

• Ludmila Pawlikowska

  132 shared

• Pui‐Yan Kwok

  Institute of Biomedical Sciences, Academia Sinica

  119 shared

• Issam A. Awad

  University of Chicago

  115 shared

• Robert Shenkar

  University of Chicago

  112 shared

• Charles E. McCulloch

  111 shared

Labs

• Marchuk LabPI