ALK1 Ligand Research Articles

Blood flow regulates acvrl1 transcription via ligand-dependent Alk1 activity.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by the development of arteriovenous malformations (AVMs) that can result in significant morbidity and mortality. HHT is caused primarily by mutations in bone morphogenetic protein receptors ACVRL1/ALK1, a signaling receptor, or endoglin (ENG), an accessory receptor. Because overexpression of Acvrl1 prevents AVM development in both Acvrl1 and Eng null mice, enhancing ACVRL1 expression may be a promising approach to development of targeted therapies for HHT. Therefore, we sought to understand the molecular mechanism of ACVRL1 regulation. We previously demonstrated in zebrafish embryos that acvrl1 is predominantly expressed in arterial endothelial cells and that expression requires blood flow. Here, we document that flow dependence exhibits regional heterogeneity and that acvrl1 expression is rapidly restored after reinitiation of flow. Furthermore, we find that acvrl1 expression is significantly decreased in mutants that lack the circulating Alk1 ligand, Bmp10, and that, in the absence of flow, intravascular injection of BMP10 or the related ligand, BMP9, restores acvrl1 expression in an Alk1-dependent manner. Using a transgenic acvrl1:egfp reporter line, we find that flow and Bmp10 regulate acvrl1 at the level of transcription. Finally, we observe similar ALK1 ligand-dependent increases in ACVRL1 in human endothelial cells subjected to shear stress. These data suggest that ligand-dependent Alk1 activity acts downstream of blood flow to maintain or enhance acvrl1 expression via a positive feedback mechanism, and that ALK1 activating therapeutics may have dual functionality by increasing both ALK1 signaling flux and ACVRL1 expression.

ALK1 Deficiency Impairs the Wound-Healing Process and Increases Mortality in Murine Model of Myocardial Infarction.

The functional role of TGFβ type I receptor, activin-like kinase (ALK)-1 in post-myocardial infarction (MI) cardiac remodeling is unknown. We hypothesize that reduced ALK1 activity reduces survival and promotes cardiac fibrosis after MI. MI was induced in wild-type (WT), and ALK+/- mice by left coronary ligation. After 14 days ALK1+/- mice had reduced survival with a higher rate of cardiac rupture compared to WT mice. ALK1+/- left ventricles (LVs) had increased volumes at the end of systole and at the end of diastole. After MI ALK1+/- LVs had increased profibrotic SMAD3 signaling, type 1 collagen, and fibrosis as well as increased levels of TGFβ1 co-receptor, endoglin, VEGF, and ALK1 ligands BMP9 and BMP10. ALK1+/- LVs had decreased levels of stromal-derived factor 1α. These data identify the critical role of ALK1 in post-MI survival and cardiac remodeling and implicate ALK1 as a potential therapeutic target to improve survival after MI.

BMP9 signaling promotes the normalization of tumor blood vessels.

The presence of an immature tumor vascular network contributes to cancer dissemination and the development of resistance to therapies. Strategies to normalize the tumor vasculature are therefore of significant therapeutic interest for cancer treatments. VEGF inhibitors are used clinically to normalize tumor blood vessels. However, the time frame and dosage of these inhibitors required to achieve normalization is rather narrow, and there is a need to identify additional signaling targets to attain vascular normalization. In addition to VEGF, the endothelial-specific receptor Alk1 plays a critical role in vascular development and promotes vascular remodeling and maturation. Therefore, we sought to evaluate the effects of the Alk1 ligand BMP9 on tumor vascular formation. BMP9 overexpression in Lewis Lung Carcinoma (LLC) tumors significantly delayed tumor growth. Blood vessels in BMP9-overexpressing LLC tumors displayed markers of vascular maturation and were characterized by increased perivascular cell coverage. Tumor vasculature normalization was associated with decreased permeability and increased perfusion. These changes in vascular function in BMP9-overexpressing LLC tumors resulted in significant alterations of the tumor microenvironment, characterized by a decrease in hypoxia and an increase in immune infiltration. In conclusion, we show that BMP9 promotes vascular normalization in LLC tumors that leads to changes in the microenvironment.

BMP10-mediated ALK1 signaling is continuously required for vascular development and maintenance.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant vascular disorder characterized by development of high-flow arteriovenous malformations (AVMs) that can lead to stroke or high-output heart failure. HHT2 is caused by heterozygous mutations in ACVRL1, which encodes an endothelial cell bone morphogenetic protein (BMP) receptor, ALK1. BMP9 and BMP10 are established ALK1 ligands. However, the unique and overlapping roles of these ligands remain poorly understood. To define the physiologically relevant ALK1 ligand(s) required for vascular development and maintenance, we generated zebrafish harboring mutations in bmp9 and duplicate BMP10 paralogs, bmp10 and bmp10-like. bmp9 mutants survive to adulthood with no overt phenotype. In contrast, combined loss of bmp10 and bmp10-like results in embryonic lethal cranial AVMs indistinguishable from acvrl1 mutants. However, despite embryonic functional redundancy of bmp10 and bmp10-like, bmp10 encodes the only required Alk1 ligand in the juvenile-to-adult period. bmp10 mutants exhibit blood vessel abnormalities in anterior skin and liver, heart dysmorphology, and premature death, and vascular defects correlate with increased cardiac output. Together, our findings support a unique role for Bmp10 as a non-redundant Alk1 ligand required to maintain the post-embryonic vasculature and establish zebrafish bmp10 mutants as a model for AVM-associated high-output heart failure, which is an increasingly recognized complication of severe liver involvement in HHT2.

Immunohistochemical Analysis of Activin Receptor-Like Kinase 1 (ACVRL1/ALK1) Expression in the Rat and Human Hippocampus: Decline in CA3 During Progression of Alzheimer's Disease.

The pathophysiology of Alzheimer's disease (AD) includes signaling defects mediated by the transforming growth factor β-bone morphogenetic protein-growth and differentiation factor (TGFβ-BMP-GDF) family of proteins. In animal models of AD, administration of BMP9/GDF2 improves memory and reduces amyloidosis. The best characterized type I receptor of BMP9 is ALK1. We characterized ALK1 expression in the hippocampus using immunohistochemistry. In the rat, ALK1 immunoreactivity was found in CA pyramidal neurons, most frequently and robustly in the CA2 and CA3 fields. In addition, there were sporadic ALK1-immunoreactive cells in the stratum oriens, mainly in CA1. The ALK1 expression pattern in human hippocampus was similar to that of rat. Pyramidal neurons within the CA2, CA3, and CA4 were strongly ALK1-immunoreactive in hippocampi of cognitively intact subjects with no neurofibrillary tangles. ALK1 signal was found in the axons of alveus and fimbria, and in the neuropil across CA fields. Relatively strongest ALK1 neuropil signal was observed in CA1 where pyramidal neurons were occasionally ALK1-immunoractive. As in the rat, horizontally oriented neurons in the stratum oriens of CA1 were both ALK1- and GAD67-immunoreactive. Analysis of ALK1 immunoreactivity across stages of AD pathology revealed that disease progression was characterized by overall reduction of the ALK1 signal in CA3 in advanced, but not early, stages of AD. These data suggest that the CA3 pyramidal neurons may remain responsive to the ALK1 ligands, e.g., BMP9, during initial stages of AD and that ALK1 may constitute a therapeutic target in early and moderate AD.

Expression of TGFβ-family signalling components in ageing cartilage: age-related loss of TGFβ and BMP receptors

Ageing is the main risk factor for osteoarthritis (OA). We investigated if expression of transforming growth factor β (TGFβ)-family components, a family which is crucial for the maintenance of healthy articular cartilage, is altered during ageing in cartilage. Moreover, we investigated the functional significance of selected age-related changes. Age-related changes in expression of TGFβ-family members were analysed by quantitative PCR in healthy articular cartilage obtained from 42 cows (age: ¾-10 years). To obtain functional insight of selected changes, cartilage explants were stimulated with TGFβ1 or bone morphogenetic protein (BMP) 9, and TGFβ1 and BMP response genes were measured. Age-related cartilage thinning and loss of collagen type 2a1 expression (∼256-fold) was observed, validating our data set for studying ageing in cartilage. Expression of the TGFβ-family type I receptors; bAlk2, bAlk3, bAlk4 and bAlk5 dropped significantly with advancing age, whereas bAlk1 expression did not. Of the type II receptors, expression of bBmpr2 decreased significantly. Type III receptor expression was unaffected by ageing. Expression of the ligands bTgfb1 and bGdf5 also decreased with age. In explants, an age-related decrease in TGFβ1-response was observed for the pSmad3-dependent gene bSerpine1 (P=0.016). In contrast, ageing did not affect BMP9 signalling, an Alk1 ligand, as measured by expression of the pSmad1/5 dependent gene bId1. Ageing negatively affects both the TGFβ-ALK5 and BMP-BMPR signalling routes, and aged chondrocytes display a lowered pSmad3-dependent response to TGFβ1. Because pSmad3 signalling is essential for cartilage homeostasis, we propose that this change contributes to OA development.

Serum induces transcription of Hey1 and Hey2 genes by Alk1 but not Notch signaling in endothelial cells.

The transcriptional repressors Hey1 and Hey2 are primary target genes of Notch signaling in the cardiovascular system and induction of Hey gene expression is often interpreted as activation of Notch signaling. Here we report that treatment of primary human endothelial cells with serum or fresh growth medium led to a strong wave of Hey1 and Hey2 transcription lasting for approximately three hours. Transcription of other Notch target genes (Hes1, Hes5, ephrinB2, Dll4) was however not induced by serum in endothelial cells. Gamma secretase inhibition or expression of dominant-negative MAML1 did not prevent the induction of Hey genes indicating that canonical Notch signaling is dispensable. Pretreatment with soluble BMP receptor Alk1, but not Alk3, abolished Hey gene induction by serum. Consequently, the Alk1 ligand BMP9 stimulated Hey gene induction in endothelial cells. Several other cell types however did not show such a strong BMP signaling and consequently only a very mild induction of Hey genes. Taken together, the experiments revealed that bone morphogenic proteins within the serum of cell culture medium are potent inducers of endothelial Hey1 and Hey2 gene expression within the first few hours after medium change.

Dalantercept. ALK-1 ligand trap, Angiogenesis inhibitor, treatment of solid tumors

Dalantercept. ALK-1 ligand trap, Angiogenesis inhibitor, treatment of solid tumors

BMP-9 regulates the osteoblastic differentiation and calcification of vascular smooth muscle cells through an ALK1 mediated pathway.

The process of vascular calcification shares many similarities with that of physiological skeletal mineralization, and involves the deposition of hydroxyapatite crystals in arteries. However, the cellular mechanisms responsible have yet to be fully explained. Bone morphogenetic protein (BMP-9) has been shown to exert direct effects on both bone development and vascular function. In the present study, we have investigated the role of BMP-9 in vascular smooth muscle cell (VSMC) calcification. Vessel calcification in chronic kidney disease (CKD) begins pre-dialysis, with factors specific to the dialysis milieu triggering accelerated calcification. Intriguingly, BMP-9 was markedly elevated in serum from CKD children on dialysis. Furthermore, in vitro studies revealed that BMP-9 treatment causes a significant increase in VSMC calcium content, alkaline phosphatase (ALP) activity and mRNA expression of osteogenic markers. BMP-9-induced calcium deposition was significantly reduced following treatment with the ALP inhibitor 2,5-Dimethoxy-N-(quinolin-3-yl) benzenesulfonamide confirming the mediatory role of ALP in this process. The inhibition of ALK1 signalling using a soluble chimeric protein significantly reduced calcium deposition and ALP activity, confirming that BMP-9 is a physiological ALK1 ligand. Signal transduction studies revealed that BMP-9 induced Smad2, Smad3 and Smad1/5/8 phosphorylation. As these Smad proteins directly bind to Smad4 to activate target genes, siRNA studies were subsequently undertaken to examine the functional role of Smad4 in VSMC calcification. Smad4-siRNA transfection induced a significant reduction in ALP activity and calcium deposition. These novel data demonstrate that BMP-9 induces VSMC osteogenic differentiation and calcification via ALK1, Smad and ALP dependent mechanisms. This may identify new potential therapeutic strategies for clinical intervention.

The type I TGFß receptor ALK‐1 and it’s ligands promote angiogenesis (544.2)

Control of angiogenesis is critical in diseases such as cancer, heart disease, or wound repair. Growth factors such as transforming growth factor beta (TGFß) and fibroblast growth factor 2 (FGF‐2) contribute to angiogenesis. The TGFß family signaling receptor Activin‐Like Kinase 1 Receptor (ALK‐1) is expressed in coronary venular endothelial cells (CVEC) at near confluent cell densities on gelatin, but not collagen but it is induced by TGFß + FGF‐2 during tube formation in collagen. Other genes induced during tube formation were Smad 6 and Fibroblast Growth Factor Receptor 1 (FGFR1). By contrast, ALK‐5, a related TGFß type 1 receptor, and TGFßRII were expressed in these cells in both gelatin and collagen. ALK‐1 is also expressed in other EC types, smooth muscle cells, cardiac fibroblasts, embryonic fibroblasts (3T3) but not epithelial cells. Three ligands: TGFß, activin, and bone morphogenetic protein 9 (BMP‐9), have been shown to bind ALK‐1. We show that endogenous activin binds ALK 1 and can be displaced by exogenous TGFß. It may function to regulate control of ALK 1 activation. The response of endothelial cells to various ALK‐1 ligands may depend on the cell matrix of endothelial cells and which other co‐receptors (type II receptors and endoglin) are expressed. We are: 1) testing expression of various ALK‐1 ligands and co‐receptors in endothelial cells under various conditions; and 2) we are generating mutants of ALK‐1, ALK‐5, and endoglin to further test their roles in angiogenesis.Grant Funding Source: Research support was from AHA‐TX and Dept Veteran’s Affairs grants (JH)

Age-related loss of the transforming growth factor β receptor ALK5 precedes osteoarthritis development in cartilage

Introduction: Osteoarthritis (OA) is the most common joint disease and (old) age is its main risk factor. One of OA's main hallmarks is degradation of articular cartilage. TGFβ-superfamily signaling plays an important role in cartilage homeostasis and maintenance via induction of Smad phosphorylation (pSmad). pSmad2/3 is a potent inhibitor of chondrocyte terminal differentiation and cell death, whereas pSmad1/5/8 induces these processes. In cartilage, two TGFβ receptors that induce Smad phosphorylation are ALK for Smad1/5/8 and ALK5 for Smad2/3. Previously, we have shown an age-related shift in receptor balance towards dominant Alk1 expression compared to Alk5 expression, and linked elevated Alk1 levels to increased Mmp13 and ColX expression and cartilage damage. However, OA development and ageing are concomitant in mice, and possibly both processes interfere. To uncouple ageing and OA-related processes, we investigated if age-related changes in TGFβ-superfamily signaling occur without interference of the OA process, and if these changes result in an altered cellular response to growth factors. We chose healthy bovine cartilage explants as a model system because bovine samples can be obtained in a wide age range without concurrent OA development. Methods: From the metacarpophalangeal joint of cows (Bos Taurus) (< 3 h post mortem), full thickness cartilage explants were collected. Macroscopically none of the animals showed any signs of OA. Samples were either immediately frozen in liquid nitrogen or, after 24 h equilibration in serum free medium, stimulated with growth factors for 24 h. Subsequently, mRNA was isolated and gene expression was measured by qPCR, using cDNA specific primers and SYBR-green. Results: Gene expression analysis of bovine explants ranging from 0.5 up to 12 years old showed a very significant 128-fold (R = 0.68, p < 0.0001) decrease in Col2a1 expression (fig. 1A) and a 3-fold decrease in Tgfb1 (R = 0.3, p = 0.002) expression with increasing age compared to 4 reference genes; Gapdh, Rpl22, Rps14 and Gusb. Furthermore, Alk5 expression decreased 4-fold (R = 0.3, p = 0.0004) whereas Alk1 expression remained unchanged. These changes in receptor level were reflected in cellular response to growth factors. Over the course of 8 years, expression of the Smad2/3p response gene Serpine1 (Pai1) became 11fold less ( p = 0.01) responsive to 1 ng/ml of the ALK5 ligand TGFβ1 (fig. 1B). In contrast, the response of 8 year old cartilage to the ALK1 ligand BMP9 (5 ng/ml) was not significantly different compared to 1 year old cartilage as measured by expression of the Smad1/5/8 response gene Id-1 (fig. 1C).

Abstract 363: Activin receptor-like kinase 1 (Alk1) ligands modulate endothelial cell function in vitro and in vivo.

Abstract The TGF-ß type-1 receptor activin receptor-like kinase 1 (Alk1) is predominantly expressed on endothelial cells, regulates vascular morphogenesis, and has been implicated in pathological angiogenesis. Alk1 expression is increased in the vasculature of a broad range of tumours and agents that disrupt of Alk1 signalling in tumour endothelial cells may be potential therapeutics for the treatment of a variety of solid tumours. Alk1 has been described as a receptor for the bone morphogenic proteins, BMP9 and BMP10. In order to study the effects of Alk1 signalling in endothelial cells in vitro and in the vasculature in vivo we used a soluble antagonist Alk1-Fc protein consisting of the extracellular domain of the Alk1 protein fused to the Fc domain of IgG1. In vitro, Alk1-Fc inhibited BMP9-dependent Alk1 signalling via phosphorylation and nuclear translocation of SMAD1/5 in endothelial cells and modulated endothelial cell functions such as an ability to form tube- like structures. In mice, physiological levels of BMP9 could be detected in serum by ELISA, consistent with detectable levels of phosphorylated SMAD1/5 in the lung, a site of high Alk1 vascular expression. In mice, the administration of Alk1-Fc effectively blocked SMAD1/5 phosphorylation in the lung, suggesting that in this tissue Alk1 ligands are the predominant driver of lung SMAD1/5 activation and that signalling is efficiently antagonised by Alk1-Fc. Despite suppression of Alk1 signalling in the lung and expression of Alk1 on the vasculature associated with tumours, Alk1-Fc did not have profound effects on tumour size or microvessel density in mice bearing tumours, however administration of Alk1-Fc in neonatal mice did cause defects in angiogenesis of the retinal vasculature demonstrating that in some contexts Alk1 ligands play an important role in regulating the angiogenic process. Citation Format: Gareth C. Davies, James A. Harper, Richard C. Sainson, Lee Brown, Grace Opoku-Ansah, Alison Smith, Matthew McCourt, James W. Legg. Activin receptor-like kinase 1 (Alk1) ligands modulate endothelial cell function in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 363. doi:10.1158/1538-7445.AM2013-363

BMP9 induces EphrinB2 expression in endothelial cells through an Alk1-BMPRII/ActRII-ID1/ID3-dependent pathway: implications for hereditary hemorrhagic telangiectasia type II

ALK1 (ACVRL1) is a member of the TGFβ receptor family and is expressed predominantly by arterial endothelial cells (EC). Mutations in ACVRL1 are responsible for hereditary hemorrhagic telangiectasia type 2 (HHT2), a disease manifesting as fragile vessels, capillary overgrowth, and numerous arterio-venous malformations. Arterial EC also express EphrinB2, which has multiple roles in vascular development and angiogenesis and is known to be reduced in ACVRL1 knockout mice. Using an in vitro angiogenesis model we find that the Alk1 ligand BMP9 induces EphrinB2 in EC, and this is entirely dependent on expression of Alk1 and at least one of the co-receptors BMPRII or ActRII. BMP9 induces both ID1 and ID3, and both are necessary for full induction of EphrinB2. Loss of Alk1 or EphrinB2 results in increased arterial-venous anastomosis, while loss of Alk1 but not EphrinB2 results in increased VEGFR2 expression and enhanced capillary sprouting. Conversely, BMP9 blocks EC sprouting and this is dependent on Alk1, BMPRII/ActRII and ID1/ID3. Finally, notch signaling overcomes the loss of Alk1-restoring EphrinB2 expression in EC, and curbing excess sprouting. Thus, in an in vitro model of HHT2, loss of Alk1 blocks BMP9 signaling, resulting in reduced EphrinB2 expression, enhanced VEGFR2 expression, and misregulated EC sprouting and anastomosis.

Abstract SY16-04: Contrasting effects of TGF-β signaling in the proangiogenic tumor stroma

Abstract Cancer results from the concerted performance of tumor cells interacting with their microenvironment. The formation of a reactive stroma evidently contributes to tumor initiation, growth and progression by providing growth-regulatory factors, supporting tumor angiogenesis, and facilitating invasion. As a rich source of cancer-promoting factors, the tumor stroma is an underestimated target for the development of novel therapeutics. Members of the transforming growth factor (TGF)-β family have been linked to vascular formation through mouse genetic studies. However, contradictory reports on the role of TGF-β signaling in physiological and pathological angiogenesis make the need for mechanistic studies apparent. Here, we describe functional studies on the role of the TGF-β receptor activin receptor-like kinase (ALK) 1 and its co-receptor endoglin in tumor angiogenesis. We demonstrate by genetic and pharmacological means that diminution of ALK1 gene dosage, or systemic treatment with an ALK1-Fc fusion protein, retarded tumor growth and progression by inhibition of angiogenesis. Moreover, we uncovered an unexpected synergy through which the combined action of different ALK1 ligands primed endothelial cells to respond to prototypical angiogenic stimuli both in vitro and in vivo. In parallel studies, genetic targeting of endoglin was revealed to give rise to an initial block in the angiogenic switch of tumors, which was overcome through acquired resistance characterized by an increased metastatic spread. The rise in metastatic dissemination was consequential to a loss of junctional patency in the endoglin-deficient vasculature due to ongoing endothelial-to-mesenchymal transition. Taken together, our studies delineate a decisive role for signaling by TGF-β family members in tumor angiogenesis and offer mechanistic insight for the forthcoming clinical development of drugs blocking TGF-β signaling in oncology. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY16-04. doi:10.1158/1538-7445.AM2011-SY16-04

ALK1 signaling regulates early postnatal lymphatic vessel development

AbstractIn vertebrates, endothelial cells form 2 hierarchical tubular networks, the blood vessels and the lymphatic vessels. Despite the difference in their structure and function and genetic programs that dictate their morphogenesis, common signaling pathways have been recognized that regulate both vascular systems. ALK1 is a member of the transforming growth factor-β type I family of receptors, and compelling genetic evidence suggests its essential role in regulating blood vascular development. Here we report that ALK1 signaling is intimately involved in lymphatic development. Lymphatic endothelial cells express key components of the ALK1 pathway and respond robustly to ALK1 ligand stimulation in vitro. Blockade of ALK1 signaling results in defective lymphatic development in multiple organs of neonatal mice. We find that ALK1 signaling regulates the differentiation of lymphatic endothelial cells to influence the lymphatic vascular development and remodeling. Furthermore, simultaneous inhibition of ALK1 pathway increases apoptosis in lymphatic vessels caused by blockade of VEGFR3 signaling. Thus, our study reveals a novel aspect of ALK1 signaling in regulating lymphatic development and suggests that targeting ALK1 pathway might provide additional control of lymphangiogenesis in human diseases.

ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2

ALK1 belongs to the type I receptor family for transforming growth factor-beta family ligands. Heterozygous ALK1 mutations cause hereditary hemorrhagic telangiectasia type 2 (HHT2), a multisystemic vascular disorder. Based largely on in vitro studies, TGF-beta1 has been considered as the most likely ALK1 ligand related to HHT, yet the identity of the physiologic ALK1 ligand remains controversial. In cultured endothelial cells, ALK1 and another TGF-beta type I receptor, ALK5, regulate angiogenesis by controlling TGF-beta signal transduction, and ALK5 is required for ALK1 signaling. However, the extent to which such interactions between these 2 receptors play a role in pathogenesis of HHT is unknown. We directly addressed these issues in vivo by comparing the phenotypes of mice in which the Alk1, Alk5, or Tgfbr2 gene was conditionally deleted in restricted vascular endothelia using a novel endothelial Cre transgenic line. Alk1-conditional deletion resulted in severe vascular malformations mimicking all pathologic features of HHT. Yet Alk5- or Tgfbr2-conditional deletion in mice, or Alk5 inhibition in zebrafish, did not affect vessel morphogenesis. These data indicate that neither ALK5 nor TGFBR2 is required for ALK1 signaling pertinent to the pathogenesis of HHT and suggest that HHT might not be a TGF-beta subfamily disease.

HHT is not a TGFβ disease

TGFβ has been considered the most likely ALK1 ligand related to hemorrhagic telangiectasia (HHT). New research reports that TGFβR2 and ALK5 are not required for HHT disease suggesting that HHT might not be a TGFβ subfamily disease.