Abstract Body: Progranulin (PGRN), an anti-inflammatory protein produced by endothelial cells (ECs), is emerging as a key regulator of vascular homeostasis and blood pressure (BP). Our previous studies showed that hypertension (HTN) is associated with altered circulating levels of PGRN, and that global PGRN deficiency leads to elevated BP and vascular dysfunction. Given the critical role of ECs in BP control, we investigated the hypothesis that ECs respond to hypertensive stress by upregulating PGRN, thereby protecting the vasculature via activation of AMPK signaling. To test this hypothesis, we developed a novel endothelial-specific PGRN-deficient mouse model (PGRN EC^-/-) and used littermate controls with intact PGRN expression (PGRN EC^+/+) for comparison. Endothelial-specific deletion of PGRN significantly reduced the circulating PGRN levels [(ng/mL) PGRN EC^+/+: 268.2 ± 11.3 vs PGRN EC^-/-: 268.2 ± 11.3) and induced ECs dysfunction (impaired vasodilation to acetylcholine, ACh) in the mesenteric arteries (MA) of both male and female mice suggesting that ECs are a major source of PGRN and that PGRN plays a critical role in maintaining ECs function. To assess the sensitivity of ECs in producing PGRN under hypertensive conditions, ECs were treated with angiotensin II (0.1 µM/24 h), which resulted in increased PGRN levels in the culture supernatant. In vivo, aldosterone infusion (600ng/kg/day) induced ECs dysfunction, elevated BP (mmHg: 135.5 ± 5.3), and increased circulating PGRN levels in PGRN EC^+/+ mice. Notably, PGRN EC^-/- mice exhibited more severe ECs dysfunction and a greater increase in BP (mmHg: 151.0 ± 7.4), but without a corresponding rise in circulating PGRN indicating that during HTN, ECs upregulate PGRN production as a protective mechanism to limit vascular injury. To investigate the endothelial mechanism by which PGRN regulates vascular tone, we crossed global PGRN-deficient mice (PGRN KO) with mice lacking endothelial AMPK (AMPK EC^-/-) to generate a double knockout model (PGRN KO/AMPK EC^-/-). All three genotypes—PGRN KO, AMPK EC^-/-, and PGRN KO/AMPK EC^-/-—showed similarly impaired ACh response in MA. While PGRN treatment restored ECs function in PGRN KO mice, it failed to do so in PGRN KO/AMPK EC-/- mice. These findings suggest that PGRN regulates ECs function through an AMPK-dependent pathway. In conclusion, ECs increase PGRN production in response to HTN as a protective mechanism to lower BP and preserve vascular function via AMPK signaling.