VEGF regulates relative allocation of Isl1⁺ cardiac progenitors to myocardial and endocardial lineages

A fundamental issue in organogenesis is how dichotomous fate decisions are made securing proper allocation of multipotent progenitors to their respective descendants. Previous lineage tracing analyses showing Isl1⁺/VEGFR2⁺ cardiac progenitors in the second heart field give rise to both endocardium and myocardium suggest VEGF plays a role in this fate decision, conceivably promoting an endocardial fate. Isl1⁺ multipotent progenitors and lineage-committed descendants thereof were visualized and quantified within their transition zone in the outflow tract. Forced VEGF expression during the critical E8.5–E10.5 interval tilted the balance between myocardial- and endocardial-committed progenitors towards the latter, culminating in generation of surplus endocardium developing at the expense of a much thinner myocardium. Experiments ruled-out that surplus endocardium is due to VEGF-induced endocardial proliferation and that reduced myocardium is due to myocardial apoptosis. Inducing VEGF after most Isl1⁺ progenitors have been exhausted had no effect on the normal endocardia/myocardial ratio but instead produced an unrelated coronary phenotype. Together, these results uncover a novel role for VEGF in controlling proper allocation of Isl1⁺ cardiac progenitors to their respective descending lineages.