Decreased potential for lymphatic vessel generation is a hallmark of early diagnosed arterial hypertension and can be reversed by treatment with angiotensin converting enzyme inhibitors

Arterial hypertension is the main risk factor for cardiovascular diseases. It is characterized by inflammation and impaired generation of blood microvasculature leading to organ damage. While the immune system is an important actor involved in both phenomena, we hypothesized that hypertensive patients show alterations in numbers of regulatory T cells (Tregs) and proangiogenic CD31 + CXCR4+ T cell subsets, which lead to alterations in serum cytokine pattern and decreased generation of blood and lymphatic vessels. Sixteen recently diagnosed hypertensive patients before treatment implementation were enrolled and followed-up for 2 years. Control group comprised of 14 healthy individuals. Each patient underwent echocardiography, eye fundus examination, optical coherence tomography, impedance cardiography, 24-hour blood pressure monitoring and central arterial pressure waveform analysis. Th and Treg cells double positive for CD31 and CXCR4, as well as subsets of naive and memory Tregs were analyzed with flow cytometry. The patients' serum cytokine pattern was defined with Luminex and ELISA. Functional in vivo assay enabled evaluation of pro-angiogenic and pro-lymphangiogenic activity of the patients' sera before and after hypotensive treatment implementation. Serum of recently diagnosed hypertensive patients showed decreased potential for generation of new lymphatic vessels in animal model. Two years after treatment implementation, the lymphangiogenic potential of the patients' sera was restored only in patients treated with angiotensin converting enzyme inhibitors (ACEI). Increased capacity for lymphatic vessel formation was associated with improved renal function (decreased microalbuminuria, increased GFR). Increased lymphangiogenic potential of the serum in hypertensive patients was associated with its cytokine profile, notably increased concentrations of VEGF-C and MDC (CCL22) and decreased levels of MIP-1α and MIP-1β. Therapy with ACEI prevented also loss of CD31 + CXCR4+ Th and CD31 + CXCR4+ Treg cells which correlated with better renal function and lower stiffness of vessel wall. Lower numbers of all Tregs and shift from Tcm to Tem phenotype in Treg population were a hallmark of fast progression of microangiopathies in hypertensive patients not treated with ACEI. In conclusion, our data indicate that early diagnosed arterial hypertension is characterized by decreased potential for lymphatic vessel generation . However, it can be reversed by ACEI implementation leading to improved renal function, lower stiffness of vessel wall and preservation of anti-inflammatory and proangiogenic T cell subsets. The current study sheds new light on interactions between immune system and lymphangiogenesis in hypertension. Therapy with ACEI may prevent or significantly delay development of vascular complications in hypertension.