Fibroblast growth factor 2 (FGF2) signaling is involved in angiogenesis, vascular contractility, and cardiac hypertrophy. Mice lacking a functionalFGF2gene (FGF2−/−) are hypotensive, but the primary physiological role of FGF2 in cardiovascular homeostasis remained unknown. Using a chickenFGF2(cFGF2) transgene under control of theWnt-1promotor, we selectively re-expressed FGF2 in the developing nervous system of FGF2−/−(transgenic FGF2 mutant) embryos. Expression of thecFGF2transgene in the developing nervous system, including its autonomic region, was limited to the period between embryonic day 9.5 and 14.5. Significantly, noFGF2re-expression was detected in developing heart and blood vessels. Pharmacological analysis revealed a normalization of the blood pressure response to isoproterenol-induced vasodilation in adult transgenic FGF2 mutant mice. In addition, the hypotensive phenotype was rescued in 1 line (of 2) transgenic FGF2 mutant adult mice having expressed higher levels of cFGF2 proteins during nervous system development. These genetic studies indicate that FGF2 signaling is essential for complete development of the neural circuitry required for central regulation of blood pressure, whereas it appears dispensable for blood pressure control in the healthy adult. The full text of this article is available at http://www.circresaha.org.