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The L-type calcium channel CaV1.2 (LTCC) is essential for vascular smooth muscle (VSM) contraction and blood pressure control. Increased vascular contractility, blood pressure, and enhanced angiotensin II (angII) signaling are hallmarks of hypertension (HTN). It has been proposed that spatial redistribution of CaV1.2 channels at the sarcolemma of VSM contributes to the potentiation of LTCC function and vascular dysfunction during HTN. However, the mechanisms underlying the spatiotemporal regulation of the CaV1.2 channels during angII signaling and HTN are poorly understood. Here, we hypothesize that CaV1.2 phosphorylation at the S1928 site is a key event mediating increased CaV1.2 channel clustering, which in turn leads to an increase in LTCC activity and vascular reactivity during angII signaling and HTN. We first demonstrated that angII-treated wild-type (WT) mesenteric arteries display increased phosphorylation at the S1928 site. Molecularly, angII redistributed CaV1.2 into larger clusters. This was correlated with elevated VSM whole-cell L-type channel currents, global intracellular Ca2+ and contraction, increased arterial tone ex vivo and in vivo in mesenteric arteries, and altered mesenteric blood flow in arteries from WT mice. These changes were prevented or significantly ameliorated in mesenteric VSM cells and arteries from a knock-in mouse expressing a mutant CaV1.2 in which serine was replaced with alanine at position 1928 (S1928A mouse) and by PKC inhibition. In angII-induced hypertensive mice, increased CaV1.2 cluster size and channel activity, enhanced arterial tone, and mean arterial pressure in WT mice were prevented or significantly reduced in S1928A mice. Altogether, these results suggest a key role for the phosphorylation of vascular CaV1.2 at S1928 in regulating LTCC spatial distribution, activity and vascular function during angII signaling and HTN. Phosphorylation of this single amino acid could be an essential regulatory mechanism that could be exploited for therapeutic intervention. This work was supported by NIH grants R01HL149127, R01HL121059, and R01HL161872 (to MFN). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.