Hypertension remains a leading cause of global morbidity and mortality, with a persistently high rate of inadequate blood pressure (BP) control despite numerous pharmacological advances in treatment. In this context, a recent study by Taguchi et al. [1] presents compelling evidence that the skin, long regarded as a passive barrier organ, actively contributes to systemic BP regulation via its local renin-angiotensin system (RAS), involving angiotensin II type 1 receptor-associated protein (ATRAP). ATRAP inhibits pathological angiotensin II (Ang II) type 1 receptor (AT1R) signaling by promoting receptor internalization [2]. In their study, human skin samples demonstrated a significant inverse correlation between ATRAP (Agtrap) mRNA expression and systolic BP, suggesting the clinical importance of ATRAP in BP regulation.

The authors further explored this mechanism using keratinocyte-specific ATRAP knockout (KO) mice model. When challenged with Ang II infusion, these mice exhibited exaggerated BP elevation compared to controls. This was accompanied by marked cutaneous vasoconstriction and increased skin expression of angiotensinogen and Ang II proteins, indicating that ATRAP deficiency enhances local RAS activation in the skin. Importantly, the hypertensive phenotype was reversed by either systemic angiotensin II receptor blocker (ARB) administration or keratinocyte-specific deletion of AT1R, supporting the existence of a feed-forward keratinocyte-specific Ang II–AT1R–angiotensinogen loop. This regulatory loop mirrors the paradigm of tissue-specific RAS circuits, such as the intrarenal RAS, where the local generation of Ang II plays a critical role in hypertension and organ damage, independent of circulating RAS activity [3].

This study provides several novel insights into this area. First, it confirms that skin RAS activity, previously implicated in wound healing and fibrosis, can influence systemic BP; independent of the classical systemic or renal RAS pathways. Second, the authors elegantly dissect the mechanism, showing that the augmented hypertensive response in keratinocyte-specific ATRAP KO mice can be completely abolished by keratinocyte-specific AT1R deletion or systemic ARB treatment. Ang II infusion significantly increased the expression of angiotensinogen and Ang II in keratinocytes, reinforcing the presence of a functional local feedback system. These observations support the concept of the skin RAS as a key modulator of systemic vascular resistance.

Of particular interest, this study revealed that cutaneous vasoconstriction, rather than sodium storage, is a key mediator of hypertension in this model. Ang II-infused ATRAP KO mice exhibited reduced transepidermal water loss (TEWL) and diminished cutaneous blood flow, effects that were normalized by heat-induced vasodilation (Fig. 1). These findings redefine the skin’s vascular bed as a novel component in BP regulation, challenging sodium-centric paradigms of hypertension pathogenesis [4]. Thus, evidence suggests that under certain conditions, such as ATRAP deficiency or enhanced skin RAS activity, cutaneous vascular tone can significantly influence systemic hemodynamics.

Fig. 1
figure 1

ATRAP and the Skin Renin-Angiotensin System: From Mechanism to Therapeutic Modulation of Hypertension. This schematic illustrates the proposed mechanism by which ATRAP (Angiotensin II type 1 receptor-associated protein) regulates cutaneous RAS activity and contributes to systemic blood pressure (BP) regulation. Under physiological conditions, ATRAP promotes internalization of the angiotensin II type 1 receptor (AT1R) in keratinocytes, thereby attenuating Ang II–mediated signaling and limiting local RAS activation. In keratinocyte-specific ATRAP deficiency, AT1R internalization is impaired, leading to sustained Ang II signaling, increased expression of angiotensinogen and Ang II in the skin, and enhanced vasoconstriction in the cutaneous vascular bed. This vasoconstriction reduces cutaneous blood flow and transepidermal water loss (TEWL), thereby contributing to systemic BP elevation. The model also highlights the therapeutic potential of transdermal ARBs, Rho kinase (ROCK) inhibitors, and skin-warming therapy, which can normalize vascular tone and mitigate Ang II-induced hypertensive responses. These findings position the skin RAS as a novel and accessible target for antihypertensive intervention, particularly in treatment-resistant hypertension

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Mechanistically, these changes may involve RhoA-mediated pathways. Upon Ang II binding to AT1R, the RhoA guanine nucleotide exchange factor Arhgef1 is activated, leading to RhoA activation and sustained myosin light chain (MLC) phosphorylation, which promotes smooth muscle contraction and BP elevation. A pivotal study by Guilluy et al. [5] demonstrated that RhoA activation in vascular smooth muscle cells is essential for Ang II-induced hypertension. Although Taguchi et al. did not directly measure RhoA signaling in the cutaneous vasculature, their findings of enhanced vasoconstriction and BP elevation in ATRAP-deficient mice are strongly consistent with the involvement of RhoA-dependent mechanisms. These results also raise the possibility that Rho kinase (ROCK) inhibition may mitigate Ang II-induced skin vasoconstriction. Experimental studies have demonstrated the dermatological applications of ROCK inhibitors. Topical fasudil reduces fibrosis and wound contraction, while Y-27632 enhances keratinocyte proliferation and migration, promoting wound healing in murine models [6]. These findings support the translational potential of local ROCK inhibition in modulating cutaneous vascular tone.

Importantly, this study suggests a paradigm shift by emphasizing the active endocrine and vascular regulatory roles of the skin in systemic BP control. If validated in human populations, targeting cutaneous RAS components, such as ATRAP or AT1R, may offer a complementary therapeutic strategy, particularly for treatment-resistant hypertension. Notably, transdermal delivery of ARBs has been shown to reduce BP in animal models, further supporting the feasibility of such interventions [7].

However, several questions remain. The suppression of Ang II-induced hypertension by body heating involves vasodilation in multiple tissues, not solely in the skin. Thus, the specific contribution of the cutaneous vasculature to thermoregulatory BP changes warrants further clarification.

In addition, the role of skin RAS in clinical phenotypes, such as salt-sensitive, obesity-related, and aging-associated hypertension, remains unclear. For example, obesity is associated with reduced ATRAP expression and systemic RAS activation. Conversely, in aged mice, systemic RAS tends to be suppressed; however, a high-salt intake enhances renal vascular Ang II sensitivity, increases vasoconstriction, and elevates BP [8]. Clarifying the role of skin RAS in these pathophysiological contexts may open new avenues for skin-targeted antihypertensive therapies.

The interplay between the skin RAS and immune cells, particularly macrophages and T cells, is an area of growing interest. Enhanced RAS signaling in keratinocytes may influence immune cell activation, thereby promoting systemic inflammation and vascular dysfunction. Indeed, previous studies have demonstrated that T cell–specific AT1R deletion significantly attenuates Ang II–induced hypertension, highlighting the central role of T cells in BP regulation through RAS signaling [9]. In contrast, macrophage-specific AT1R deletion appears to primarily reduce vascular inflammation and oxidative stress, with more modest effects on BP. These findings underscore the cell type-specific contributions of immune AT1R signaling to the pathophysiology of hypertension.

Furthermore, emerging technologies, such as single-cell RNA sequencing and spatial transcriptomics, can be leveraged to dissect the cellular architecture and signaling networks within the skin microenvironment. These tools may uncover novel cell populations or signaling gradients involved in skin RAS activation and its systemic effects. Understanding how environmental factors, such as temperature, humidity, and mechanical stress, modulate skin RAS activity may provide new insights into BP regulation.

In conclusion, this landmark study by Taguchi et al. redefined the skin as an active player in the systemic BP homeostasis. By identifying ATRAP–AT1R signaling in keratinocytes as a critical determinant of Ang II–induced hypertension, the authors provide compelling evidence that the skin RAS functions as an autonomous and therapeutically targetable regulator of vascular tone. These findings pave the way for future research and therapeutic development, including transdermal or topical agents that modulate skin RAS activity (Fig. 1). As we seek novel strategies for managing resistant hypertension, the skin, which has long been overlooked in cardiovascular physiology, may emerge as a promising and accessible therapeutic target.