The lymphatic vasculature plays an important role in mediating fluid balance and local inflammation in many tissues and organs throughout the body (Huang et al., 2017; Oliver et al., 2020). The heart also carries a complex lymphatic network and relies on cardiac lymphatics to drain interstitial fluids and immune cells for maintaining homeostasis (Brakenhielm and Alitalo, 2019). Disrupting cardiac lymphatics can cause myocardial edema and lead to impaired cardiac function (Cui et al., 2001; Mehlhorn et al., 1995), indicating a critical role of cardiac lymphatics in cardiovascular physiology. Recently, cardiac lymphatics have emerged as a new therapeutic target for acute cardiac injuries. Several studies have demonstrated using rodent models that therapeutic lymphangiogenesis reduced myocardial edema and fibrosis, resolved inflammation, and improved cardiac function after myocardial infarction (Henri et al., 2016; Houssari et al., 2020; Klotz et al., 2015; Tatin et al., 2017; Trincot et al., 2019; Vieira et al., 2018) or ischemia and reperfusion injury (Shimizu et al., 2018). These studies in aggregate concluded that the improvement in cardiac function was due to local proliferation of lymphatic vessels at the site of injury in response to lymphangiogenic therapies. Importantly, these animal models represent cardiac injuries, in which blood and lymphatic vessels are surgically manipulated. However, the role of the lymphatic vasculature in the pathogenesis of chronic cardiac dysfunction and the effects of lymphangiogenic therapies on cardiac dysfunction remain to be explored. Here, we explored the role of the lymphatic vasculature in cardiac dysfunction and investigated the effects of a lymphangiogenic therapy (VEGFCc156s) on the angiotensin II infusion-induced cardiac dysfunction model. We found that angiotensin II infusion-induced cardiac dysfunction is associated with impaired lymphatic vascular function as well as increased cardiac fibrosis and inflammation, whereas VEGFCc156s treatment ameliorated these pathologies. Interestingly, angiotensin II-infused mice treated with VEGFCc156s also demonstrated a delayed and dramatic response to reverse angiotensin II-induced hypertension. Thus, we propose that the beneficial effects of the lymphangiogenic therapy VEGFCc156s on angiotensin II infusion-induced cardiac dysfunction are multifaceted and mediated by its concomitant effects on cardiac lymphatic function, inflammatory and fibrotic gene expression, and systemic hypertension.

Recent studies indicated that the lymphatic vasculature, a traditionally-neglected target for therapeutic interventions, plays an important role in the pathogenesis of cardiovascular diseases, and enhancing lymphangiogenesis could be beneficial for acute cardiac injuries (Henri et al., 2016; Houssari et al., 2020; Huang et al., 2017; Klotz et al., 2015; Liu and Oliver, 2019; Shimizu et al., 2018; Tatin et al., 2017; Trincot et al., 2019; Vieira et al., 2018; Vivien et al., 2019). However, the role of the lymphatic vasculature in chronic cardiac dysfunction remains to be elucidated. In this study, we aimed to investigate the role of the lymphatic vasculature in the pathogenesis of chronic heart failure and cardiac dysfunction. We found several SNPs near lymphatic marker gene loci that were associated with human cardiovascular or metabolic comorbidities in human GWAS studies, although some of the associations did not meet the genome-wide threshold and some of the loci are close to another gene in addition to the lymphatic endothelial marker (Table 1). To validate the findings from the GWAS analysis, we conducted expression profiling using human heart samples and found reduced expression of lymphatic endothelial markers in human chronic heart failure hearts (Figure 1), suggesting that the lymphatic vasculature may play a role in the pathogenesis of human chronic heart failure and cardiac dysfunction. Our observations are in line with previously published RNA sequencing analyses of human hearts (Sweet et al., 2018; van Heesch et al., 2019) and a recent clinical report indicating that serum VEGFC levels are significantly and inversely associated with all-cause and cardiovascular death (Wada et al., 2018), supporting a role of lymphatic vasculature in the pathogenesis of cardiovascular diseases. However, previous reports found minimal changes in lymphatic vascular density in left ventricular endomyocardial biopsies from terminal heart failure hearts and healthy donor hearts using immunohistochemistry (Dashkevich et al., 2009; Dashkevich et al., 2010). Thus, further investigations are required to characterize the changes in lymphatic vasculature in human chronic heart failure pathogenesis.

Using a murine model of cardiac dysfunction, we demonstrate that a chronic cardiac insult such as angiotensin II infusion induced lymphatic vascular dysfunction by reducing lymphatic vascular density (Figure 2) and impairing lymphatic vascular transport function in the heart (Figure 3). Podoplanin is widely used as a marker for LECs and is preferentially expressed in pre-collectors and collectors of the cardiac lymphatic vasculature (Henri et al., 2016). A previous study demonstrated that enhancing lymphangiogenesis by over-expressing VEGFC with adenoviruses in a mouse model of lymphedema induced robust growth of lymphatic capillaries in axillary tissues after 2 weeks but failed to improve lymphatic vascular leakage, while with prolonged VEGFC stimulation (2–6 months), the lymphatic capillaries underwent an intrinsic remodeling and maturation and became functional collecting vessels, leading to reduced tissue edema and restored lymphatic drainage (Norrmén et al., 2011; Tammela et al., 2007). Moreover, VEGFCc156s can reportedly directly enhance lymphatic pump activity and lymphatic output in rat mesentery collecting lymphatics (Breslin et al., 2007), indicating a potential direct beneficial effect of VEGFCc156s on lymphatic vascular function in addition to its role in enhancing lymphangiogenesis and maturation. Here, consistent with these previous reports, we observed that 6 week continuous infusion of VEGFCc156s concomitant with angiotensin II restored collecting vessel function and improved cardiac lymphatic drainage, leading to improved cardiac fluid balance regulation. Myocardial edema is a key clinical feature of cardiac dysfunction and chronic heart failure, and heart function could be significantly compromised with a subtle increase in interstitial fluid volume (Dongaonkar et al., 2010). Therefore, the improved cardiac lymphatic vascular function and tissue fluid homeostasis in the VEGFCc156s-treated, angiotensin II-infused animals might contribute to the improved cardiac function and reduced cardiac hypertrophy observed. One area for future investigation is a further characterization of the changes in cardiac lymphatic valves, which play an important role in regulating the lymph flow in collecting vessels. In addition, podoplanin, a marker of lymphatic collecting vessels, is also reportedly expressed in inflammatory cells. Previous reports indicated that a high frequency of podoplanin-expressing cells appeared in the infarcted heart and facilitated local inflammation, and podoplanin neutralization improved cardiac function after myocardial infarction (Cimini et al., 2017; Cimini et al., 2019; Quintanilla et al., 2019). In our study, we assessed podoplanin-expressing lymphatic vessels but not other podoplanin-expressing cells; further analysis of other podoplanin-expressing cells in our disease model would be an area for future investigation.

Previous studies have demonstrated impairments in the lymphatic vasculature in a myocardial infarction model, where the left anterior descending artery is surgically ligated (Henri et al., 2016; Klotz et al., 2015). Importantly, the lymphatic vessel parallel to this major blood vessel is likely also mechanically impaired by this surgical manipulation, thus testing the hypothesis that mechanical disruption of the lymphatic vasculature can impair heart function, and regrowth using lymphangiogenic therapy is beneficial. Our observations are in line with these previous studies; however, the studies presented herein importantly assess lymphatic dysfunction in the absence of direct injury or surgical manipulation. Likely the impairments in lymphatic vascular function observed in angiotensin II-infused mice could come directly from angiotensin II actions on the endothelium, as angiotensin II can induce endothelial dysfunction (Gomolak and Didion, 2014; Watanabe et al., 2005) or perhaps indirectly from angiotensin II infusion-induced hypertension, which reportedly alters lymphatic vascular function (Dongaonkar et al., 2015).

The lymphatic vasculature also plays an important role in mediating local inflammation (Brakenhielm and Alitalo, 2019), and in acute cardiac injury models, resolution of inflammation following lymphangiogenic therapy has been proposed to be an underlying therapeutic mechanism (Tatin et al., 2017; Vieira et al., 2018). Our RNA-seq analysis indicated that LECs expressed proinflammatory chemokines after angiotensin II stimulation (Figure 4), which is consistent with previous reports indicating a role of angiotensin II in initiating inflammatory and chemotactic responses in tissues and vasculature (Benigni et al., 2010; Suzuki et al., 2003). Interestingly, VEGFCc156s treatment alleviated the inflammatory responses induced by angiotensin II infusion in LECs by reducing the expression of proinflammatory chemokines, which may contribute to the beneficial effects of VEGFCc156s on angiotensin II-induced cardiac dysfunction. Our results are in line with a previous report indicating that VEGFCc156s treatment downregulated the expression of genes involved in immune regulation and inflammation in dermal LECs without stress or stimulation (Dieterich et al., 2017), while here we report that VEGFCc156s treatment ameliorated inflammatory responses in LECs under stress (angiotensin II infusion). Moreover, the transcriptional changes in LECs detected by RNA-seq analysis translated to tissue and systemic levels, and we observed elevations in chemokine levels in skin and plasma in angiotensin II-infused mice, which were alleviated by VEGFCc156s treatment. These results in aggregate suggest that lymphatic vessels may play a more active role in mediating local and systemic inflammation than simply providing a route for immune cell clearance, and VEGFCc156s may directly alleviate systemic inflammation through transcriptional effects on LECs.

More interestingly, upon VEGFCc156s treatment, a significant reduction of angiotensin II-induced increases in blood pressure and kidney damage was observed (Figure 5 and Figure 6). Our observations are in line with a previous report indicating that the treatment of VEGFC, a ligand for both VEGFR2 and VEGFR3, also induced a delayed systemic hemodynamic response to reduce blood pressure and attenuated related renal damage in a high-salt induced hypertension model (Beaini et al., 2019). Our study used VEGFCc156s, a ligand with specificity for VEGFR3, suggesting that VEGFC-mediated effects are indeed mediated by VEGFR3 activation. Furthermore, these effects are not limited to salt-induced pathology, as VEGFCc156s also ameliorated angiotensin II-induced hypertension and renal damage, suggesting that VEGFC may play a broad role to modulate hypertension. Moreover, in line with the observations using the murine models, a recent clinical study also showed that patients with hypertension have significantly lower serum VEGFC levels compared with healthy individuals (Chachaj et al., 2018), supporting a potential role of lymphatic vasculature in the pathogenesis of human hypertension. Hypertension is a major risk factor for heart failure and other cardiovascular diseases (Dorans et al., 2018; Tackling and Borhade, 2019), and anti-hypertensive therapies significantly reduce cardiovascular events and mortality in patients in clinical studies (Ettehad et al., 2016). Therefore, the effect of VEGFCc156s on blood pressure might also contribute significantly to its beneficial effects on angiotensin II-induced cardiac dysfunction.

Consistent with previous reports regarding the role of renal lymphatics in the pathogenesis of hypertension (Balasubbramanian et al., 2020; Lopez Gelston et al., 2018), we also observed an endogenous expansion of renal lymphatics in response to angiotensin II-induced hypertension (Figure 6). The previous reports also demonstrated that enhancing renal lymphatic expansion by over-expressing VEGFD prevented the development of hypertension. Therefore, we initially hypothesized that VEGFCc156s might enhance the endogenous renal lymphangiogenesis response and thus ameliorate angiotensin II infusion-induced hypertension. Surprisingly, no lymphangiogenic response was observed in the kidney of VEGFCc156s-treated angiotensin II-infused animals at both the 1-week and 6-week time points assessed here (Figure 6E and F, Figure 6—figure supplement 1E–1H and Figure 7—figure supplement 1F–1H). Thus, it is possible that the lymphangiogenesis response we observed in the kidney of angiotensin II-infused mice could be an adaptation to hypertension and was therefore ameliorated in VEGFCc156s-treated, angiotensin II-infused mice at the 6-week timepoint due to reduced blood pressure. In the previous reports, the authors used a transgenic line to over-express VEGFD by 800-fold over baseline specifically in kidney and observed significant expansion of renal lymphatics, while our study used VEGFCc156s at a low dose that only increased plasma VEGFC levels by 1.6-fold to 1.9-fold on average. In addition, as a low-molecular weight protein, VEGFCc156s will be quickly filtered through glomeruli followed by adsorptive endocytosis and lysosomal degradation (Franssen et al., 1994), resulting in poor local retention and exposure of VEGFCc156s in kidney. Therefore, the discrepancy between our study and previous studies could possibly be explained by differences in local exposure of the lymphangiogenic factors with transgenic overexpression and chronic systemic administration.

Although VEGFCc156s significantly ameliorated angiotensin II-induced hypertension, the underlying molecular mechanisms remain to be explored. We first carefully examined the possibility that VEGFCc156s interfered with angiotensin II-mediated effects, and several lines of evidence in our studies indicate that there were no alterations in angiotensin II-mediated vascular effects after VEGFCc156s treatment, as angiotensin II caused aortic remodeling (Figure 5F), induced vascular leakage (Figure 3B) and vascular hypertrophy (Figure 6—figure supplement 1A) and increased renal Ace2 expression (Figure 5G and Figure 7—figure supplement 1D) similarly in both the angiotensin II-infused and the VEGFCc156s-treated, angiotensin II-infused group, indicating that angiotensin II acted as a vasoactive molecule in both groups. In addition, causal reasoning analysis of RNA-seq data also pointed at angiotensin II as a causal factor for the changes observed in cardiomyocytes from both the angiotensin II-infused and the VEGFCc156s-treated, angiotensin II-infused group. Finally, the similar blood pressure elevations detected in the first week in both angiotensin II-infused and VEGFCc156s-treated, angiotensin II-infused groups indicated successful release of angiotensin II from the pumps in both groups (Figure 5). Therefore, we suggest that VEGFCc156s did not interfere with angiotensin II effects to alleviate the phenotypes in this disease model. Another possibility is that VEGFCc156s might affect the skin lymphatic vasculature to regulate blood pressure, as skin lymphatics have been implicated as a potential disease-modifying factor in the pathogenesis of salt-sensitive hypertension (Karlsen et al., 2018). After 6 weeks of treatment, VEGFCc156s significantly increased skin lymphatic vessel density and diameter in angiotensin II-infused mice (Figure 2—figure supplement 1O–1R); these changes may contribute to the reductions observed in blood pressure in these animals. Further investigations are needed to fully characterize the molecular mechanisms underlying the beneficial effect of VEGFCc156s on angiotensin II-induced hypertension.

To dissect the potential direct effect of VEGFCc156s on the heart from its effect on blood pressure, we examined the effects of VEGFCc156s in angiotensin II-infused mice at 1 week after treatment, at which timepoint the blood pressure was similarly high in animals treated with angiotensin II alone or a combination of angiotensin II and VEGFCc156s (Figure 5). Although VEGFCc156s treatment enhanced podoplanin-positive lymphatic vessel growth in the heart at this timepoint, it did not alleviate cardiac hypertrophy in angiotensin II-infused mice. More interestingly, VEGFCc156s treatment restored angiotensin II-induced pro-fibrotic and pro-inflammatory markers in angiotensin II-infused hearts in gene expression analyses and immunohistochemistry staining, indicating a beneficial effect of VEGFCc156s in a blood pressure-independent manner (Figure 7 and Figure 7—figure supplements 1 and 2). The lymphatic vasculature has been proposed to play an important role in regulating myocardial fibrosis (Brakenhielm et al., 2020) and a previous report indicated that lymphangiogenic factor treatment in a rat model of myocardial infarction improved cardiac function by reducing cardiac fibrosis (Henri et al., 2016). Our results are in line with this previous report, as VEGFCc156s also reduced cardiac fibrosis in angiotensin II-infused mice as early as 1 week post-treatment, which may contribute to the efficacy we observed at the 6-week timepoint.

In summary, our study demonstrates that lymphatic vessels are impaired in cardiac dysfunction, and the lymphangiogenic therapy VEGFCc156s prevented cardiac dysfunction by improving lymphatic vascular function, alleviating cardiac fibrosis and inflammation, and ameliorating hypertension. These results provide new insights into the potential effects of a lymphangiogenic therapy on chronic cardiac diseases and underlying mechanisms and indicate that the lymphatic vasculature could be a therapeutic target for hypertension and hypertensive heart disease.

RNA-Seq data has been deposited in GEO under accession code GSE150041. All other data generated during the study are included in the manuscript and supporting files. Source data has been provided for Figure 1-7.

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Author details

1. LouJin Song

   Internal Medicine Research Unit, Pfizer Inc, Cambridge, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Writing - original draft, Writing - review and editing

   Competing interests

   is an employee at Pfizer inc

   "This ORCID iD identifies the author of this article:" 0000-0002-1646-8121

2. Xian Chen

   1. Comparative Medicine, Pfizer Inc, Cambridge, United States
   2. Drug Safety Research & Development, Pfizer Inc, Groton, United States

   Contribution

   Investigation

   Competing interests

   is an employee at Pfizer inc

3. Terri A Swanson

   Early Clinical Development, Pfizer Inc, Cambridge, United States

   Contribution

   Investigation

   Competing interests

   is an employee at Pfizer inc

4. Brianna LaViolette

   Comparative Medicine, Pfizer Inc, Cambridge, United States

   Contribution

   Investigation

   Competing interests

   is an employee at Pfizer inc

5. Jincheng Pang

   Internal Medicine Research Unit, Pfizer Inc, Cambridge, United States

   Contribution

   Formal analysis, Methodology

   Competing interests

   is an employee at Pfizer inc

6. Teresa Cunio

   1. Internal Medicine Research Unit, Pfizer Inc, Cambridge, United States
   2. Acceleron Pharma, Cambridge, United States

   Present address

   Acceleron Pharmaceuticals

   Contribution

   Investigation

   Competing interests

   was an employee at Pfizer inc and is currently an employee at Acceleron Pharma

7. Michael W Nagle

   1. Internal Medicine Research Unit, Pfizer Inc, Cambridge, United States
   2. Eisai Inc, Cambridge, United States

   Present address

   Eisai Pharmaceuticals

   Contribution

   Formal analysis, Methodology, Writing - review and editing

   Competing interests

   was an employee at Pfizer Inc and is currently an employee at Eisai Inc

8. Shoh Asano

   Internal Medicine Research Unit, Pfizer Inc, Cambridge, United States

   Contribution

   Investigation

   Competing interests

   is an employee at Pfizer Inc

9. Katherine Hales

   Internal Medicine Research Unit, Pfizer Inc, Cambridge, United States

   Contribution

   Investigation

   Competing interests

   is an employee at Pfizer Inc

10. Arun Shipstone

    Inflammation and Immunology Research Unit, Pfizer Inc, Cambridge, United States

    Contribution

    Investigation, Methodology

    Competing interests

    is an employee at Pfizer Inc

11. Hanna Sobon

    Inflammation and Immunology Research Unit, Pfizer Inc, Cambridge, United States

    Contribution

    Investigation, Methodology

    Competing interests

    is an employee at Pfizer Inc

12. Sabra D Al-Harthy

    1. Comparative Medicine, Pfizer Inc, Cambridge, United States
    2. Drug Safety Research & Development, Pfizer Inc, Groton, United States

    Contribution

    Investigation

    Competing interests

    is an employee at Pfizer Inc

13. Youngwook Ahn

    Target Sciences, Emerging Science and Innovation, Pfizer Inc, Cambridge, United States

    Contribution

    Investigation, Methodology

    Competing interests

    is an employee at Pfizer Inc

14. Steven Kreuser

    Comparative Medicine, Pfizer Inc, Cambridge, United States

    Contribution

    Investigation

    Competing interests

    is an employee at Pfizer Inc

15. Andrew Robertson

    Drug Safety Research & Development, Pfizer Inc, Groton, United States

    Contribution

    Investigation

    Competing interests

    is an employee at Pfizer Inc

16. Casey Ritenour

    Drug Safety Research & Development, Pfizer Inc, Groton, United States

    Contribution

    Investigation

    Competing interests

    is an employee at Pfizer Inc

17. Frank Voigt

    Drug Safety Research & Development, Pfizer Inc, Groton, United States

    Contribution

    Investigation

    Competing interests

    is an employee at Pfizer Inc

18. Magalie Boucher

    Drug Safety Research & Development, Pfizer Inc, Groton, United States

    Contribution

    Investigation

    Competing interests

    is an employee at Pfizer Inc

19. Furong Sun

    Early Clinical Development, Pfizer Inc, Cambridge, United States

    Contribution

    Formal analysis

    Competing interests

    is an employee at Pfizer Inc

20. William C Sessa

    Department of Pharmacology, Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, United States

    Contribution

    Supervision, Visualization, Writing - review and editing

    Competing interests

    consultant for Pfizer.

    "This ORCID iD identifies the author of this article:" 0000-0001-5759-1938

21. Rachel J Roth Flach

    Internal Medicine Research Unit, Pfizer Inc, Cambridge, United States

    Contribution

    Conceptualization, Supervision, Funding acquisition, Visualization, Project administration, Writing - review and editing

    For correspondence

    Rachel.RothFlach@pfizer.com

    Competing interests

    is an employee at Pfizer Inc

    "This ORCID iD identifies the author of this article:" 0000-0003-2754-828X

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