Macrophage Programming Emerges as a Central Question in Pulmonary Arterial Hypertension
Pulmonary arterial hypertension remains difficult to reverse once distal pulmonary arteries have remodeled and the right ventricle has begun to fail. Contemporary pathway-directed therapy can improve symptoms, exercise capacity, hemodynamics, and clinical outcomes, and sotatercept has further reduced clinical worsening in treated patients, yet established vascular lesions and right ventricular dysfunction often persist. The gap between symptomatic improvement and structural reversal has pushed macrophages into the center of mechanistic debate.
Inflammation in PAH is not just present; it appears organized, localized, and potentially durable. Macrophages sit at the intersection of endothelial injury, smooth muscle proliferation, fibroblast activation, extracellular-matrix remodeling, hypoxia, altered nutrients, oxidative stress, and mechanical cues within the perivascular niche. These cells respond to those signals and send them back, shaping the vascular wall through bidirectional communication with endothelial cells, pulmonary arterial smooth muscle cells, and adventitial fibroblasts.
One striking example is monocyte-released HERV-K dUTPase, which engages TLR4 and MCAM to drive endothelial-to-mesenchymal transition. In that setting, the immune signal is not a bystander; it becomes part of the remodeling machinery.
Why Ongoing Activation Is Not the Same as Persistent Programming
The review separates three explanations for the macrophage states seen in pulmonary arterial hypertension. The first is ongoing conditioning by an abnormal niche. The second is selective recruitment of monocyte subsets that already carry inflammatory features. The third is cell-intrinsic programming that persists even after the initiating stimulus fades.
These distinctions matter because a transcriptional signature alone cannot prove durable reprogramming. Static single-cell and spatial studies can identify lesion-specific, subset-specific, and stage-specific macrophage states, but they cannot by themselves determine whether those states reflect persistent epigenetic or epitranscriptomic memory, continuous exposure to disease cues, or changing cellular composition within the lesion. A macrophage that remains inflammatory because the tissue remains hostile is biologically different from one that has been internally re-set.
The review also draws a careful line between persistent activation and trained immunity. Trained immunity requires a priming-rest-rechallenge sequence and a demonstrable enhanced secondary response after withdrawal of the original stimulus. PAH macrophages may never experience such clean separation from their niche. They may instead live in a chronically abnormal environment that sustains activation without classical immune memory.
TET2 and METTL3/m6A as Prioritized Mechanistic Axes
Among the candidate regulators, TET2 and METTL3/m6A are prioritized as experimentally tractable entry points. TET2 is positioned as a candidate route through which metabolic cues may shape DNA regulation and inflammatory restraint. METTL3-mediated m6A modification is presented as a complementary route through which metabolic states may influence RNA fate, including stability and translation.
The logic here is biologically coherent. Metabolic changes in the perivascular niche can influence chromatin and RNA regulation, and those molecular layers can lock macrophages into a particular inflammatory output. Citrate export, ATP-citrate lyase activity, glycolysis-derived lactate, one-carbon metabolism, and mitochondrial stress all provide plausible links between the environment and gene regulation. A macrophage exposed repeatedly to those cues may no longer behave like a transient responder; it may become a cell whose inflammatory thresholds have been reset.
Human genetic and expression findings support the relevance of TET2 in PAH, and Tet2-deficient pulmonary hypertension models strengthen that association. METTL3 is tied to experimental pulmonary hypertension through vascular-cell mechanisms and more recent myeloid-directed genetic and pharmacological interventions. Even so, the evidence does not establish durable programming in human lesional macrophages. The review keeps that boundary explicit.
Lesion-Resolved Biology Shows Macrophages Change With Time and Place
The pulmonary vascular lesion is not a uniform compartment. Human lung and pulmonary-vascular transcriptomic studies increasingly resolve disease-associated cellular heterogeneity, and spatial profiling shows that plexiform lesions and remodeled adventitial regions carry molecular programs distinct from control pulmonary arteries. In parallel, experimental studies have begun to separate macrophage activation state, anatomic location, and origin rather than treating macrophages as a single inert population.
Temporal analysis in hypoxic mice identified an early MHCIIhiCCR2+EAR2+ inflammatory phase followed by a TLF+VCAM1hi pro-remodeling interstitial-macrophage phase. A separate line of work showed that MHCIIhiLYVE1loCCR2hi interstitial macrophages can arise predominantly from recruited monocytes, accumulate around pulmonary arteries, and promote a fibroblast-like smooth muscle transition through WNT11–planar-cell-polarity signaling. Another study described distinct contributions from resident and recruited lung macrophages, with recruited cells acquiring a pro-inflammatory HIC1-linked program and resident cells engaging a PRRX2-associated profibrotic program.
Those observations argue against a single macrophage identity in PAH. They also suggest that treatment response may depend on which compartment is being measured. Alveolar macrophages, interstitial macrophages, perivascular macrophages, and monocyte-derived macrophages all occupy different niches and carry different developmental histories. Their lipid handling, glucose use, iron handling, scavenging functions, antigen presentation, and inflammatory potential are not interchangeable.
Right Ventricular Stress Extends the Immune Problem Beyond the Lung
The right ventricle is not a passive downstream casualty. In advanced disease, macrophage-associated inflammatory signaling extends into maladaptive right ventricular remodeling. The review treats pulmonary vascular disease and right ventricular disease separately for a reason: a mechanism that sustains vascular remodeling may not be identical to one that worsens ventricular adaptation.
This separation is clinically important. A pathway that remains active in the pulmonary perivascular niche may help explain why established disease is incompletely reversible even after targeted therapy. It may also explain why the relevant biomarker compartment matters so much. Blood, bronchoalveolar samples, and tissue biopsies provide different views of the same disease process, and none of them can stand in for the others without care.
The challenge is not simply to identify macrophages in PAH. It is to establish which macrophages, in which compartment, at which disease stage, and under which molecular control, are sustaining the remodeling program.
What Must Be Proven Before These Axes Become Therapeutic Targets
The review lays out a validation framework that is stricter than descriptive omics. To support persistent programming, experiments must show that the response survives stimulus withdrawal, account for cellular origin and turnover, and test dependence on a candidate regulator. To support trained immunity, they must go further and include a defined priming-rest-rechallenge sequence. To support translational relevance, the findings must localize to a defined vascular or right ventricular niche, map onto human lesions, and remain relevant after disease has already been established.
That bar is appropriate because current evidence is still mixed across human tissue, experimental models, and ex vivo systems. Chronic hypoxia rodent models are useful for studying hypoxia-associated inflammation and vascular muscularization, but they do not fully reproduce the plexiform and severe obliterative lesions of idiopathic human PAH. Macrophage states identified in those models may reflect hypoxia-specific adaptation rather than the full biology of human disease.
The practical implication is straightforward. TET2 and METTL3/m6A deserve focused validation, but only in designs that can distinguish persistent programming from ongoing activation, separate recruited from resident cells, and test whether established disease can actually be reversed. Without that level of proof, the field risks confusing correlation with durable control of the disease process.