NFAT Transcription Factors Emerge as Central Drivers of Pulmonary Hypertension

Pulmonary hypertension remains one of the most stubborn challenges in cardiovascular medicine, a progressive disease in which the blood vessels of the lungs narrow, stiffen, and eventually strangle the circulation that carries oxygen from the lungs to the heart. Now a comprehensive review published in Molecular Biology Reports by Jing Luo, Jianqiao Liu, Haocheng Zhang, Bang Xin, and Xiaoqin Ha of Gansu University of Chinese Medicine and the 940th Hospital of the Joint Logistics Support Force has pulled together the scattered evidence pointing to a single family of molecular culprits: the nuclear factor of activated T cells, or NFAT, transcription factors. The review, published on 10 October 2026, argues that activation of NFAT1 through NFAT4 constitutes a fundamental mechanism underlying the runaway proliferation of pulmonary artery smooth muscle cells, the cellular engine of vascular remodeling, while the role of the fifth family member, NFAT5, remains an open question.

To understand why this matters, it helps to picture what actually goes wrong in pulmonary hypertension. In healthy pulmonary arteries, smooth muscle cells embedded in the vessel wall exist in a quiescent, contractile state, squeezing and relaxing in response to physiological signals. In pulmonary hypertension, these cells undergo what biologists call phenotypic switching: they abandon their contractile identity, revert to a synthetic, proliferative state, and begin dividing relentlessly while resisting apoptosis, the normal program of cell death. The result is thickening of the vessel wall, narrowing of the lumen, and a steady rise in pulmonary vascular resistance that eventually overloads the right ventricle of the heart. Current therapies, including prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors such as sildenafil, can dilate vessels and modestly improve symptoms, but none of them halts or reverses the remodeling process itself. This is precisely the gap that NFAT-targeting strategies hope to fill.

The NFAT family comprises five proteins, NFAT1 through NFAT5, each encoded by a separate gene. The classical members, NFAT1 through NFAT4, share a distinctive mode of regulation centered on calcium. When intracellular calcium concentrations rise, the calcium-binding protein calmodulin activates the phosphatase calcineurin, which strips phosphate groups from NFAT proteins and exposes nuclear localization sequences. The dephosphorylated transcription factors migrate into the nucleus, bind to specific DNA sequences, and switch on programs of gene expression. When calcium signaling subsides, kinases rephosphorylate NFAT and export it back to the cytoplasm, shutting the switch off. This elegant cycle, first characterized in immune cells in the late 1980s, has since been recognized in vascular smooth muscle, cardiac muscle, skeletal muscle, and endothelial cells, making NFAT a versatile integrator of calcium-dependent signals across many tissues.

In the pulmonary artery, the calcium connection is critical. Multiple upstream pathways converge to elevate calcium in pulmonary artery smooth muscle cells during the development of pulmonary hypertension. Hypoxia, the hallmark stimulus of the disease, increases the activity of store-operated calcium channels through proteins such as STIM1 and STIM2, and modulates transient receptor potential channels including TRPC6, TRPV1, and TRPV4. Vasoconstrictive and mitogenic agonists such as endothelin-1, platelet-derived growth factor, serotonin, and sphingosine-1-phosphate further amplify calcium entry. Each of these inputs has been shown to feed the calcineurin-NFAT axis. When Luo and colleagues surveyed this literature, they found a consistent pattern: whatever raises cytosolic calcium in these cells ultimately drives NFAT into the nucleus, where it activates genes that promote cell-cycle progression, migration, and survival.

The specific NFAT isoforms appear to play distinct roles. NFATC2, corresponding to NFAT2, has been implicated in cyclin A expression, a gene essential for DNA synthesis and cell division. Platelet-derived growth factor, a potent mitogen in pulmonary hypertension, drives proliferation and migration of pulmonary artery smooth muscle cells in part by regulating NFATC2. NFATC1, or NFAT3 in some nomenclature conventions, targets cyclin A as well in vascular smooth muscle and has been linked to the proliferative response in restenosis, a related vascular overgrowth process. NFATC3, however, has attracted particular attention in the pulmonary circulation. Studies in mice lacking functional NFATC3 showed that this isoform is required for chronic hypoxia-induced pulmonary hypertension in both adult and neonatal animals. NFATC3 mediates the up-regulation of alpha-actin during hypoxic remodeling, contributes to the expression of collagen type V, and regulates soluble guanylyl cyclase alpha-1, a key component of the nitric oxide signaling pathway that keeps vessels dilated. Its activation can be driven not only by calcium but also by redox changes, with increased superoxide and reduced hydrogen peroxide promoting NFATC3 activation in pulmonary arterial smooth muscle.

Beyond the direct calcium route, the review highlights how NFAT sits at the downstream end of several signaling cascades already implicated in pulmonary hypertension. The STAT3/PIM-1/NFAT pathway, well known for its role in cancer cell survival, is constitutively activated in pulmonary arterial hypertension, and the nuclear receptor Nur77 suppresses smooth muscle cell proliferation by inhibiting this very axis. The kinase DYRK1A, which phosphorylates NFAT and promotes its export from the nucleus, emerged as a protective brake; inhibiting DYRK1A in experimental models actually worsened remodeling through the STAT3/PIM-1/NFAT pathway, whereas pharmacological approaches that restrain NFAT activation attenuated vascular remodeling. MicroRNAs add another layer of control: microRNA-124 suppresses NFAT transactivation by targeting multiple genes and inhibits smooth muscle cell proliferation, microRNA-204 is down-regulated in pulmonary hypertension with consequences for NFAT-driven proliferation, and microRNA-153 induces apoptosis by targeting NFATC3, improving vascular remodeling in experimental disease.

Crucially, the therapeutic implications have already been tested in animal models. The landmark demonstration came from a 2007 study showing that the nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted, establishing proof of principle that blocking NFAT activation could reverse established disease in rodents. Cyclosporin A and tacrolimus, calcineurin inhibitors used clinically as immunosuppressants in transplantation, inhibit the NFAT pathway and have been shown to attenuate hypoxia-induced pulmonary hypertension and right ventricular hypertrophy in animal studies, with case reports describing responses in patients with pulmonary arterial hypertension secondary to inflammatory conditions. Sildenafil, already approved for pulmonary arterial hypertension, was found to inhibit calcineurin/NFATC2-mediated cyclin A expression in pulmonary artery smooth muscle cells, suggesting that part of its clinical benefit may derive from previously unappreciated effects on this transcriptional pathway. Other agents with NFAT-modulating activity include docosahexaenoic acid, which inhibits hypoxia-induced phenotype switching by blocking NFATC1 signaling; dehydroepiandrosterone, which restores right ventricular structure and function in severe experimental disease; and plumbagin and parp1-modulating compounds that act through microRNA-dependent mechanisms upstream of NFAT.

The review is candid about what remains unknown. NFAT5, the most ancient family member, is fundamentally different from its relatives: it is constitutively nuclear, does not cooperate with FOS and JUN, and is regulated not by calcium but by osmotic and mechanical stress. Recent work shows that NFAT5 is indispensable for a balanced adaptive transcriptional response of lung endothelial cells to hypoxia, and that arterial wall stress controls NFAT5 activity in vascular smooth muscle, where specific isoforms govern biomechanical stress responses and flow- and pressure-induced arterial remodeling in mice. Whether NFAT5 acts as a friend or foe in pulmonary hypertension, protecting endothelial resilience or contributing to maladaptive remodeling, is a question the authors flag as unresolved. They also note broader limitations: much of the evidence comes from rodent models such as monocrotaline and Sugen/hypoxia systems, whose fidelity to human disease is imperfect, and isoform-specific functions in human pulmonary artery smooth muscle cells remain incompletely mapped.

Nevertheless, the synthesis carries a clear message for the field. The convergence of calcium overload, redox signaling, growth factor stimulation, and inflammatory cytokines on the NFAT transcription factors suggests that these proteins act as a bottleneck through which multiple pathological inputs funnel into a single proliferative output. Targeting that bottleneck, whether with existing calcineurin inhibitors repurposed for vascular disease, with isoform-selective inhibitors that spare the immune system, or with microRNA-based approaches that tune NFAT activity with greater precision, offers a route toward therapies that address vascular remodeling rather than merely dilating vessels. As the global burden of pulmonary arterial hypertension continues to grow according to recent Global Burden of Disease analyses, and as guidelines from the European Society of Cardiology and European Respiratory Society emphasize the unmet need for antiremodeling treatments, the NFAT pathway stands out as one of the most mechanistically grounded and therapeutically actionable targets on the horizon.

Subject of Research: The role of NFAT transcription factors in pulmonary artery smooth muscle cell proliferation and pulmonary vascular remodeling in pulmonary hypertension

Article Title: The critical role of NFAT transcription factors in pulmonary arterial remodeling and pulmonary hypertension: from PASMC proliferation to therapeutic targeting

Article References: Luo, J., Liu, J., Zhang, H., Xin, B., & Ha, X. (2026). The critical role of NFAT transcription factors in pulmonary arterial remodeling and pulmonary hypertension: from PASMC proliferation to therapeutic targeting. Molecular Biology Reports, 53(1), Article 1696. https://doi.org/10.1007/s11033-026-12810-x

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12810-x

Keywords: pulmonary hypertension, NFAT transcription factors, pulmonary artery smooth muscle cells, vascular remodeling, calcineurin signaling, calcium signaling, phenotypic switching, NFATC3, therapeutic targeting, microRNAs, cyclosporin A, pulmonary vascular disease