Abstract
Balanced transforming growth factor-beta (TGFβ)/bone morphogenetic protein (BMP)-signaling is essential for tissue formation and homeostasis. While gain in TGFβ signaling is often found in diseases, the underlying cellular mechanisms remain poorly defined. Here we show that the receptor BMP type 2 (BMPR2) serves as a central gatekeeper of this balance, highlighted by its deregulation in diseases such as pulmonary arterial hypertension (PAH). We show that BMPR2 deficiency in endothelial cells (ECs) does not abolish pan-BMP-SMAD1/5 responses but instead favors the formation of mixed-heteromeric receptor complexes comprising BMPR1/TGFβR1/TGFβR2 that enable enhanced cellular responses toward TGFβ. These include canonical TGFβ-SMAD2/3 and lateral TGFβ-SMAD1/5 signaling as well as formation of mixed SMAD complexes. Moreover, BMPR2-deficient cells express genes indicative of altered biophysical properties, including up-regulation of extracellular matrix (ECM) proteins such as fibrillin-1 (FBN1) and of integrins. As such, we identified accumulation of ectopic FBN1 fibers remodeled with fibronectin (FN) in junctions of BMPR2-deficient ECs. Ectopic FBN1 deposits were also found in proximity to contractile intimal cells in pulmonary artery lesions of BMPR2-deficient heritable PAH (HPAH) patients. In BMPR2-deficient cells, we show that ectopic FBN1 is accompanied by active β1-integrin highly abundant in integrin-linked kinase (ILK) mechano-complexes at cell junctions. Increased integrin-dependent adhesion, spreading, and actomyosin-dependent contractility facilitates the retrieval of active TGFβ from its latent fibrillin-bound depots. We propose that loss of BMPR2 favors endothelial-to-mesenchymal transition (EndMT) allowing cells of myo-fibroblastic character to create a vicious feed-forward process leading to hyperactivated TGFβ signaling. In summary, our findings highlight a crucial role for BMPR2 as a gatekeeper of endothelial homeostasis protecting cells from increased TGFβ responses and integrin-mediated mechano-transduction.
Highlights
Tissue homeostasis involves tight regulation and coordination of biochemical and biomechanical signaling pathways to maintain cellular identity and functionality
bone morphogenetic protein (BMP) signaling requires a complex of type-1 (BMPR1, i.e., Activin receptor-like kinase [ALK]1, 2, 3, or 6) and type-2 (i.e., BMP type-2 receptor (BMPR2), Activin A receptor, type-2 A [ACVR2A]/Activin A receptor, type-2 B [ACVR2B]) serine/threonine kinase receptors to activate Suppressor of Mothers against Decapentaplegic (SMAD) transcription factors
The main endothelial BMP-SMAD1/5 signals are induced by BMP9/10 found in human plasma [31,32], with BMP9/10 binding to its high-affinity receptor ALK1 in complex with BMPR2 and co-receptor Endoglin (ENG) [33,34,35]
Summary
Tissue homeostasis involves tight regulation and coordination of biochemical and biomechanical signaling pathways to maintain cellular identity and functionality. Balance between bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFβ) signaling is important for tissue homeostasis. For vascular homeostasis, sustained activity of BMP but only mild TGFβ signaling is required [1]. A switch of this balance to the benefit of augmented responses toward TGFβ is a hallmark of endothelial cell (EC) dysfunction and precondition to several vascular diseases, including cerebral cavernous malformation (CCM) [2], hereditary hemorrhagic telangiectasia (HHT) [3], and pulmonary arterial hypertension (PAH). Endothelial responses to TGFβ include extracellular matrix (ECM) production and endothelial-to-mesenchymal transition (EndMT), a process by which ECs lose their identity and instead adopt a mesenchymal/myo-fibroblastic character [5,6]. Endothelial BMPR2 deficiency is found in some but not all cases of idiopathic PAH (IPAH) [12,13] as well as in other vascular pathologies involving endothelial inflammation and arteriosclerosis [14] reviewed in [15]
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