Methods and Compositions for Treatment and Patient Stratification of Vascular Disease by Restoration of an Endothelial-Protective Program and Reversal of Endothelial-to-Mesenchymal Transition (Provisional Patent Specification)

Specification of U.S. Provisional Patent Application No. 64/130,015 (filed August 10, 2026; inventor Glen Charles Ritschel, Ritschel Research), archived as a citable, timestamped defensive-publication disclosure. This disclosure describes a single-cell RNA-sequencing-derived signature of a pathogenic endothelium that has lost a bone-morphogenetic-protein- and KLF2/KLF4-driven protective program and has undergone endothelial-to-mesenchymal transition (EndoMT), and a method of treating, stratifying, and restoring that cell state across a genus of vascular diseases. The two-sided EndoMT-EC signature comprises an endothelial-identity and BMP-protective down-program to be restored (PECAM1, CDH5, KLF2, KLF4, TEK, BMPR2, ID1, and related genes) and a mesenchymal and matrix up-program to be suppressed (ACTA2, TAGLN, SERPINE1, fibrillar collagens, and related genes). The state is validated in systemic sclerosis pulmonary arterial hypertension endothelium, where it is disease-distinct from idiopathic PAH with independent peer-reviewed corroboration (Tuhy et al., senior author Simpson, Circ Genom Precis Med 2025); is shared in systemic sclerosis digital vasculopathy; and is human-genetically anchored in hereditary hemorrhagic telangiectasia, a disease caused by loss-of-function mutations in ALK1 and endoglin at the top of the same BMP axis. The disclosure provides the signature and an orthogonal endothelial-protective-loss score; a method of measuring the state; a method of selecting agents that restore the protective program and reverse EndoMT (KLF2/KLF4-inducing statins and AMPK activators, ROCK2 inhibitors such as belumosudil, PPAR-gamma agonists such as pioglitazone, and BMP-receptor-pathway activators), optionally in combination with fibroblast-directed or macrophage-directed antifibrotic agents targeting the other effectors of the same disease; and a stratification biomarker defining a responder subgroup. The genus is limited to vascular diseases where loss of the program is validated or genetically established. Discovery-stage computational work; the disease-associated cell state is validated in independent human data and human genetics, while reversal by the named agents is mechanism-anchored, with a defined in-vitro pulmonary-endothelial reversal assay, and is not yet demonstrated clinically. Not medical or legal advice.