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. 2022 Oct 17;68(4):381–394. doi: 10.1165/rcmb.2022-0020OC

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Figure 1. — Tm4sf1 (transmembrane 4 L six family member 1)–marked subpopulation of endothelial cells expresses a distinct transcriptomic signature relevant to PAH. (A–F) Uniform manifold approximation and projection (UMAP) plots showing clustering of 758 endothelial cell transcriptomes from 18 rat lungs with individual cells colored by (A) subpopulation, (B) disease condition (n = 6/group), and expression amounts of the following marker genes: (C) Car4 for EC, (D) Nostrin for endothelial arterial type 1 (EA1), (E) Tm4sf1 for endothelial arterial type 2 (EA2), and (F) Sox17 as a known arterial marker expressed in both EA1 and EA2. Expression amounts are represented as log normalized counts. (G) Volcano plot showing DEGs in 255 EA2 cells compared with 454 EA1 cells, where x-axis represents MAST z-scores and y-axis indicates −log₁₀(P). Significant upregulated (z > 0) or downregulated (z < 0) genes with FDR < 0.05 are shown as purple and green dots, respectively. Select top DEGs are labeled with their gene names. DEGs highlighted in yellow represent human PAH-associated genes from either (black text) or both (red text) CTD and DisGeNET database. (H–K) Dot plots showing gene set enrichment analysis of the EA2 DEG signature using (H) GO, (I) hallmark, (J) HuBMAP, and (K) DisGeNET gene sets, where x-axis represents normalized enrichment scores (NESs) in which NES greater than or less than zero and FDR < 0.05 represent gene sets significantly enriched in up- or downregulated genes, respectively, and are colored in purple or green, respectively. The y-axis represents gene sets ordered by their NESs. Select gene sets are labeled and numbered by their ordering as top gene sets enriched in up- or downregulated genes. Dots larger in size represent higher −log₁₀(FDR) values. Acer2 = alkaline ceramidase 2; Adgrf5 = adhesion G protein-coupled receptor F5; Akap12 = A-kinase anchoring protein 12; Anxa3 = annexin A3; Aplnr = apelin receptor; Apoe = apolipoprotein E; Atf3 = activating transcription factor 3; BC028528 = cDNA sequence BC028528; Bmpr2 = bone morphogenetic protein receptor type 2; Cap = cyclase associated actin cytoskeleton regulatory protein; Car4 = carbonic anhydrase 4; Casp3 = caspase 3; Ccdc68 = coiled-coil domain containing 68; Ccnd1 = cyclin D1; Cdh5 = cadherin 5; Cdkn1a = cyclin-dependent kinase inhibitor 1A; Ch25h = cholesterol 25-hydroxylase; Clec14a = C-type lectin domain containing 14A; Cmip = c-Maf-inducing protein; Col4a1 = collagen type IV alpha 1 chain; Cst3 = cystatin C; CTD = Comparative Toxicogenomics Database; DEG = differentially expressed gene; EC = endothelial capillary; Ednrb = endothelin receptor type B; Egr1 = early growth response 1; Eln = elastin; Epas1 = endothelial PAS domain protein 1; ER = endoplasmic reticulum; Fbln = fibulin; Fbn1 = fibrillin 1; FDR = false discovery rate; Fezf2 = Fez family zinc finger 2; Fn1 = fibronectin 1; Fos = Fos protooncogene, AP-1 transcription factor subunit; Fosb = FosB protooncogene, AP-1 transcription factor subunit; Foxf1 = forkhead box F1; Gja5 = gap junction protein, alpha 5; GO = Gene Ontology; Gpx = glutathione peroxidase; Hbegf = heparin binding EGF like growth factor; Hs3st3A1 = heparan sulfate-glucosamine 3-sulfotransferase 3A1; HuBMAP = Human BioMolecular Atlas Program; Icam1 = intercellular adhesion molecule 1; Igfbp7 = insulin-like growth factor binding protein 7; Jam2 = junctional adhesion molecule 2; Junb = JunB protooncogene, AP-1 transcription factor subunit; Klf4 = KLF transcription factor 4; Linc01107 = long intergenic non–protein-coding RNA 1107; Lpl = lipoprotein lipase; MCT = monocrotaline; Mgp = matrix Gla protein; Mt2a = metallothionein 2A; Myc = MYC protooncogene, bHLH transcription factor; Myof = myoferlin; Nfkbia = NFKB inhibitor alpha; Nfkbiz = NFKB inhibitor zeta; Nostrin = nitric oxide synthase trafficking; Nuak1 = NUAK family kinase 1; PAH = pulmonary arterial hypertension; Plat = plasminogen activator, tissue type; Plvap = plasmalemma vesicle associated protein; Ppap2a = phosphatidic acid phosphatase type 2A; Procr = protein C receptor; RT1-CE4 = RT1 class I, locus CE4; S100 = S100 calcium-binding protein; Sat1 = spermidine/spermine N1-acetyl transferase 1; Sdpr = caveolae associated protein 2; Selp = selectin P; Sema3c = semaphorin 3C; Slc29a1 = solute carrier family 29 member 1; Slc6a2 = solute carrier family 6 member 2; Slfn5 = schlafen family member 5; Sox17 = SRY-box transcription factor 17; Sptbn1 = spectrin, beta, nonerythrocytic 1; Srgn = serglycin; SuHx = Sugen–hypoxia; Sulf1 = sulfatase 1; TGF = transforming growth factor; Timp3 = TIMP metallopeptidase inhibitor 3; Ucp2 = uncoupling protein 2; Vcam1 = vascular cell adhesion molecule 1; Vwf = von Willebrand factor; Wif1 = Wnt inhibitory factor 1.

Figure 1. — Tm4sf1 (transmembrane 4 L six family member 1)–marked subpopulation of endothelial cells expresses a distinct transcriptomic signature relevant to PAH. (A–F) Uniform manifold approximation and projection (UMAP) plots showing clustering of 758 endothelial cell transcriptomes from 18 rat lungs with individual cells colored by (A) subpopulation, (B) disease condition (n = 6/group), and expression amounts of the following marker genes: (C) Car4 for EC, (D) Nostrin for endothelial arterial type 1 (EA1), (E) Tm4sf1 for endothelial arterial type 2 (EA2), and (F) Sox17 as a known arterial marker expressed in both EA1 and EA2. Expression amounts are represented as log normalized counts. (G) Volcano plot showing DEGs in 255 EA2 cells compared with 454 EA1 cells, where x-axis represents MAST z-scores and y-axis indicates −log₁₀(P). Significant upregulated (z > 0) or downregulated (z < 0) genes with FDR < 0.05 are shown as purple and green dots, respectively. Select top DEGs are labeled with their gene names. DEGs highlighted in yellow represent human PAH-associated genes from either (black text) or both (red text) CTD and DisGeNET database. (H–K) Dot plots showing gene set enrichment analysis of the EA2 DEG signature using (H) GO, (I) hallmark, (J) HuBMAP, and (K) DisGeNET gene sets, where x-axis represents normalized enrichment scores (NESs) in which NES greater than or less than zero and FDR < 0.05 represent gene sets significantly enriched in up- or downregulated genes, respectively, and are colored in purple or green, respectively. The y-axis represents gene sets ordered by their NESs. Select gene sets are labeled and numbered by their ordering as top gene sets enriched in up- or downregulated genes. Dots larger in size represent higher −log₁₀(FDR) values. Acer2 = alkaline ceramidase 2; Adgrf5 = adhesion G protein-coupled receptor F5; Akap12 = A-kinase anchoring protein 12; Anxa3 = annexin A3; Aplnr = apelin receptor; Apoe = apolipoprotein E; Atf3 = activating transcription factor 3; BC028528 = cDNA sequence BC028528; Bmpr2 = bone morphogenetic protein receptor type 2; Cap = cyclase associated actin cytoskeleton regulatory protein; Car4 = carbonic anhydrase 4; Casp3 = caspase 3; Ccdc68 = coiled-coil domain containing 68; Ccnd1 = cyclin D1; Cdh5 = cadherin 5; Cdkn1a = cyclin-dependent kinase inhibitor 1A; Ch25h = cholesterol 25-hydroxylase; Clec14a = C-type lectin domain containing 14A; Cmip = c-Maf-inducing protein; Col4a1 = collagen type IV alpha 1 chain; Cst3 = cystatin C; CTD = Comparative Toxicogenomics Database; DEG = differentially expressed gene; EC = endothelial capillary; Ednrb = endothelin receptor type B; Egr1 = early growth response 1; Eln = elastin; Epas1 = endothelial PAS domain protein 1; ER = endoplasmic reticulum; Fbln = fibulin; Fbn1 = fibrillin 1; FDR = false discovery rate; Fezf2 = Fez family zinc finger 2; Fn1 = fibronectin 1; Fos = Fos protooncogene, AP-1 transcription factor subunit; Fosb = FosB protooncogene, AP-1 transcription factor subunit; Foxf1 = forkhead box F1; Gja5 = gap junction protein, alpha 5; GO = Gene Ontology; Gpx = glutathione peroxidase; Hbegf = heparin binding EGF like growth factor; Hs3st3A1 = heparan sulfate-glucosamine 3-sulfotransferase 3A1; HuBMAP = Human BioMolecular Atlas Program; Icam1 = intercellular adhesion molecule 1; Igfbp7 = insulin-like growth factor binding protein 7; Jam2 = junctional adhesion molecule 2; Junb = JunB protooncogene, AP-1 transcription factor subunit; Klf4 = KLF transcription factor 4; Linc01107 = long intergenic non–protein-coding RNA 1107; Lpl = lipoprotein lipase; MCT = monocrotaline; Mgp = matrix Gla protein; Mt2a = metallothionein 2A; Myc = MYC protooncogene, bHLH transcription factor; Myof = myoferlin; Nfkbia = NFKB inhibitor alpha; Nfkbiz = NFKB inhibitor zeta; Nostrin = nitric oxide synthase trafficking; Nuak1 = NUAK family kinase 1; PAH = pulmonary arterial hypertension; Plat = plasminogen activator, tissue type; Plvap = plasmalemma vesicle associated protein; Ppap2a = phosphatidic acid phosphatase type 2A; Procr = protein C receptor; RT1-CE4 = RT1 class I, locus CE4; S100 = S100 calcium-binding protein; Sat1 = spermidine/spermine N1-acetyl transferase 1; Sdpr = caveolae associated protein 2; Selp = selectin P; Sema3c = semaphorin 3C; Slc29a1 = solute carrier family 29 member 1; Slc6a2 = solute carrier family 6 member 2; Slfn5 = schlafen family member 5; Sox17 = SRY-box transcription factor 17; Sptbn1 = spectrin, beta, nonerythrocytic 1; Srgn = serglycin; SuHx = Sugen–hypoxia; Sulf1 = sulfatase 1; TGF = transforming growth factor; Timp3 = TIMP metallopeptidase inhibitor 3; Ucp2 = uncoupling protein 2; Vcam1 = vascular cell adhesion molecule 1; Vwf = von Willebrand factor; Wif1 = Wnt inhibitory factor 1.